AU782977B2 - Methods for regulating gastrointestinal motility - Google Patents

Description

S&F Ref: 452630D1

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

ORIGINAL

Name and Address of Applicant: Actual Inventor(s): Address for Service: Invention Title: Amylin Pharmaceuticals, Inc.

9373 Towne Centre Drive San Diego California 92121 United States of America Andrew A.Young, Bronislava Gedulin, Nigel Robert Arnold Beeley, Kathryn S. Prickett Spruson Ferguson St Martins Tower,Level 31 Market Street Sydney NSW 2000 (CCN 3710000177) Methods for Regulating Gastrointestinal Motility description of this invention, including the best method of The following statement is a full performing it known to me/us:- 5845c Methods For Regulating Gastrointestinal Motility Field of the Invention The present invention relates to methods for regulating gastrointestinal motility. More particularly, the invention relates to the use of exendins and analogs and agonists thereof for the treatment of disorders which would be benefited with agents useful in delaying and/or slowing gastric emptying.

Background The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art to to the presently claimed invention, nor that any of the publications specifically or implicitly referenced are prior art to that invention.

Publications and other materials including patents and patent applications used to illuminate :the specification are hereby incorporated by reference.

Exendin 15 The exendins are peptides that are found in the venom of the Gila-monster, a lizard found in Arizona. Exendin-3 [SEQ. ID. NO. 1] is present in the venom of 6 *o [R:\LIBAA]31 696.doc:MCN He-idrma horridium, and exendin-4 [SEQ. ID. NO. 2] is present in the venom of Helnderma quqpcrtiiM (Eng, et al., T- Rin61 rhem., 265:20259-62, 1990; Eng., et al., j ic-A. Chern., 267:7402-05, 1992). The exendins have some sequ~ence similarity to several members of the glucagon-like peptide family, with the highest homology, 53%, being to GLP-1t?7-36]NH, (Goke, et al., J_ ioL- Chein., 268:19650-55, 1993). GLP-1[7-36]NH 2 [SEQ. ID. NO.

3] is also known as proglucagon[78-107], or simply the shorthand "GLP-l," which is used interchangeably;.Nwj thrGLP- 1[7-36]NH, throughout this application. The sequences of exendin-3, exendin-4 and GLP-l are shown in Figure 1.

GLP-l has an insulinotropic effect, stimulating insulin secretion from pancreatic n-cells; GLP-1 also inhibits 15 glucagon secretion from pancreatic ci-cells (0rskov, et al., Djabttes-, 42:658-61,- 1993; D'Alessio, et al., JL *Clin. TnvFe.-t-., 97:133-38, 1996). GLP-l is reported to inhibit gastric emptying (Willms B, et al., J.C-lin Rrirrinnl Metah 81 327-32, 1996; Wettergren A, et al., Digq ni~ A i 38 665-73, 1993) and gastric acid secretion. Schjoldager BT, et al., Dig nis Spi34 703-8, 1989; O'Halloran DJ, et al., J Endocrino] 126 169-73, 1990; Wettergren A, et al., Dig Dis Srci 38 :665-73, 1993). GLP-l[7-37], which has an additional glycine residue at its carboxy terminus, also stimulates insulin secretion in humans (0rskov, et al., Diabe-t-s;, 42:658-61, 1993).

A transmembrane G-p~rotein adenylate- cyclase -coupled receptor believed to be responsible for the insulinotropic effect of GLP-I has been cloned from a 3-cell line (Thorens, Proc. Natl. Acad. Sci. USA 89:8641-45 (1992), hereinafter referred to as the "cloned GLP-1 receptor.

3 Exendin-4 is reportedly a potent agonist at GLP-1 receptors on insulin-secreting PTC1 cells, at dispersed acinar cells from guinea pig- pancreas, and at parietal cells from stomach; the peptide is also reported to stimulate somatostatin release and inhibit gastrin release in isolated stomachs (Goke, et al., J. Biol. Chem.

268:19650-55, 1993; Schepp, et al., Eur. J. Pharmacol., 69:183-91, 1994; Eissele, et al., Life Sci., 55:629-34, 1994). Exendin-3 and exendin-4 were found to be GLP-1 agonist5 ir inTbimulating cAMP production in, and amylase release from, pancreatic acinar cells (Malhotra, et al., Regulatory Peptides,41:149-56, 1992; Raufman, et al., Biol. Chem. 267:21432-37, 1992; Singh, et al., Regul.

e. ppt. 53:47-59, 1994). Based on the insulinotropic 15 activities of exendin-3 and exendin-4, their use has been proposed for the treatment of diabetes mellitus and the prevention of hyperglycemia (Eng, U.S. Patent No.

5,424,286).

•In contrast to the full-length exendins, truncated exendin peptides such as exendin[9-39], a carboxyamidated molecule, and fragments 3-39 through 9-39 of exendin have been reported to be potent and selective antagonists of GLP-1 (Goke, et al., J. Biol. Chem., 268:19650-55, 1993; Schepp, et al., Eur. J. Pharm. 269:183-91, 1994; 25 Montrose-Rafizadeh, et al., Diabetes,45(Suppl. 2):152A, 1996). Exendin[9-39], the sequence of which is shown in Figure 1, reportedly blocks endogenous GLP-1 in vivo, resulting in reduced insulin secretion. Wang, et al., J.

Clin. Invest., 95:417-21, 1995; D'Alessio, et al., JL Clin. Invest., 97:133-38, 1996). Exendins and exendin[9-39] bind to the cloned GLP-1 receptor (Fehmann HC, et al., Peptides 15 453-6, 1994; Thorens B, et al., Diabetes 42 1678-82, 1993). In cells transfected with the cloned GLP-1 receptor, exendin-4 is an agonist, it increases cAMP, while exendin[9-39] is an antagonist, it blocks the stimulatory actions of exendin-4 and GLP-1.

Exendin[9-39] is also reported to act as an antagonist of the full length exendins, inhibiting stimulation of pancreatic acinar cells by exendin 3 and exendin 4 (Raufman, et al., J. Biol. Chem. 266:2897-902, 1991; Raufman, et al., J. Biol. Chem., 266:21432-37, 1992). Exendin[9-39] is said to inhibit the stimulation of plasma insulin levels by exendin 4, and inhibits the somatostatin release-stimulating and gastrin releaseinhibiting activities of exendin-4 and GLP-1 (Kolligs, F., 15 et al., Diabetes, 44:16-19, 1995; Eissele, et al., Life Sciences, 55:629-34, 1994).

Agents which serve to delay gastric emptying have found a place in medicine as diagnostic aids in gastrointestinal radiologic examinations. For example, glucagon 20 is a polypeptide hormone which is produced by the a cells of the pancreatic islets of Langerhans. It is a hyperglycaemic agent which mobilizes glucose by activating hepatic glycogenolysis. It can to a lesser extent stimulate the secretion of pancreatic insulin. Glucagon 25 is used in the treatment of insulin-induced hypoglycaemia when administration of glucose intravenously is not possible. However, as glucagon reduces the motility of the gastro-intestinal tract it is also used as a diagnostic aid in gastro-intestinal radiological examinations. Glucagon has also been used in several studies to treat various painful gastro-intestinal disorders associated with spasm. Daniel, et al. (Br. Med.

3r 1974, 3, 720) reported quicker symptomatic relief of acute diverticulitis in patients treated with glucagon compared with those who had been treated with analgesics or antispasmodics. A review by Glauser, et al., (JL.Am- Coll Emrgenry Physns, 8:228, 1979) described relief of acute oesophageal food obstruction following glucagon therapy. In another study glucagon significantly relieved pain and tenderness in 21 patients with biliary tract disease compared with 22 patients treated with placebo S 10 Stower, et al., Br. J_ Surg., 69:591-2, 1982).

Methods for regulating gastrointestinal motility using amylin agonists are described in International Application No. PCT/US94/10225, published March 16, 1995.

RSUMMARY OF THF TNVENTTON 15 The present invention concerns the surprising S discovery that exendins are potent inhibitors of gastric emptying. Exendins and exendin agonists are useful as inhibitors of gastric emptying for the treatment of, for example, diabetes mellitus, obesity, the ingestion of toxins, or for diagnostic purposes.

The present invention is directed to novel methods for reducing gastric motility and slowing gastric emptying, comprising the administration of an exendin, for example, exendin 3 [SEQ ID NO. exendin 4 [SEQ ID NO.

or other compounds which effectively bind to the receptor at which exendins exert their action on gastric motility and gastric emptying. These methods will be useful in the treatment of, for example, post-prandial hyperglycemia, a complication associated with type 1 (insulin dependent) and type 2 (non-insulin dependent) diabetes mellitus.

i i~i i In a first aspect, the invention features a method of beneficially regulating gastrointensional motility in a subject by administering to said subject a therapeutically effective amount of an exendin or an exendin agonist, with the proviso that the exendin agonist is not glucagon-like peptide 1. By "exendin agonist" is meant a compound which mimics the effects of exendins on s gastric motility and gastric emptying, namely, a compound which effectively binds to the receptor at which exendins exert their action on gastric motility and gastric emptying, preferably an analog or derivative of an exendin.

Exendin agonist compounds useful in present invention include those compounds of the formula [SEQ. ID. NO. 4]: 1 5 Xaa, Xaa 2 Xaa 3 Gly Thr Xaa 4 Xaa 5 Xaa 6 Xaa7 Xaa 8 Ser Lys Gin Xaa 9 Glu Glu Glu Ala Val Arg Leu Xaalo Xaa, Xaa 12 Xaa 1 3 Leu Lys Asn Gly Gly Xaa 14 Ser Ser Gly Ala Xaa 15 Xaa 1 6 Xaa 1 7 Xaals-Z wherein Xaai is His, Arg or Tyr; Xaa2 is Ser, Gly, Ala or Thr; Xaa3 is Asp or Glu4; Xaa is Phe, Tyr or naphthalanine; Xaas is Thr or Ser; Xaas is Ser or Thr; Xaa7 is Asp or Glu; Xaa8 is Leu, lie, Val, pentylglycine or Met; Xaa9 is Leu, lie, pentylglycine, Val or Met; Xaaio is Phe,Tyr or naphthalanine; Xaaii is lie, Val, Leu, pentylglycine, tert-butylglycine or Met; Xaal2 is Glu or Asp; Xaal3 is Trp, Phe, 15 Tyr, or naphthylalanine; Xaal4, Xaais, Xaa16 and Xaa17 are independently Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine or N-alkylalanine; Xaals is Ser, Thr or Tyr; and Z is -OH or -NH2; with the proviso that the compound does not have the formula of either SEQ. ID. NOS. 1 or 2. Also useful in the present invention are pharmaceutically acceptable salts of the compounds of formula In one embodiment, the methods of the present invention are directed to reducing gastric motility. In another embodiment, the invention is directed to methods of delaying gastric emptying.

These methods may be used on a subject undergoing a gastrointensional diagnostic procedure, for example radiological examination or magnetic resonance imaging. Alternatively, these methods may be used to reduce gastric motility in a subject suffering from a gastro-intestinal disorder, for example, spasm (which may be associated with acute diverticulitis, a disorder of the biliary tract or a disorder of the Sphincter of Oddi). In another aspect, the invention is directed to a method of treating post-prandial dumping syndrome in a subject by administering to the subject a therapeutically effective amount of an exendin or exendin agonist.

[R:\LIBAA]31696.doc:MCN -7- Accordingly, in another aspect there is provided a method of treating a disease or disorder which may be benefited by a decrease in gastrointestinal motility or a delay in gastric emptying in a subject, the method comprising administering to said subject a therapeutically effective amount of an exendin or exendin agonist that provides for the reduction in gastric motility or delay in gastric emptying, wherein the disease or disorder is postprandial dumping syndrome and with the proviso that the exendin agonist is not glucagon-like peptide 1.

In yet another aspect, there is provided an exendin or exendin agonist when used for treating a disease or disorder which may be benefited by a decrease in gastrointestinal to motility or a delay in gastric emptying wherein the disease or disorder is post-prandial dumping syndrome and with the proviso that the exendin agonist is not glucagon-like peptide 1.

In yet another aspect, there is provided the use of an exendin or exendin agonist in the manufacture of a medicament for treating a disease or disorder which may be benefited by a decrease in gastrointestinal motility or a delay in gastric emptying wherein the disease or disorder is post-prandial dumping syndrome and with the proviso that the exendin agonist is not glucagon-like peptide 1.

In yet another aspect, there is provided a method of treating a disease or disorder which may be benefited by a decrease in gastrointestinal motility or a delay in gastric 20 emptying in a subject, the method comprising administering to the subject a therapeutically effective amount of an exendin or exendin agonist that provides for the reduction in gastric motility or delay in gastric emptying, wherein the disease or disorder is postprandial hyperglycemia that is benefited by a decrease in gastrointestinal motility or a delay in gastric emptying, with the proviso that the exendin agonist is not glucagon-like peptide 1.

25 In yet another aspect, there is provided an exendin or exendin agonist when used for treating a disease or disorder which may be benefited by a decrease in gastrointestinal motility or a delay in gastric emptying wherein the disease or disorder is postprandial i ~hyperglycemia that is benefited by a decrease in gastrointestinal motility or a delay in gastric emptying, with the proviso that the exendin agonist is not glucagon-like peptide 1.

[R:\LIBZ\Vaughan\Prosecutions\452630D I]452630D I.RL2.consistories.doc:VNB -7a In yet another aspect, there is provided the use of an exendin or exendin agonist in the manufacture of a medicament for treating a disease or disorder which may be benefited by a decrease in gastrointestinal motility or a delay in gastric emptying wherein the disease or disorder is postprandial hyperglycemia that is benefited by a decrease in gastrointestinal motility or a delay in gastric emptying, with the proviso that the exendin agonist is not glucagon-like peptide 1.

In yet another aspect, there is provided a method of treating type 1 diabetes mellitus in a subject, the method comprising administering to the subject a therapeutically effective amount of an exendin or an exendin agonist, wherein said exendin agonist is selected from a peptide compound of the formula: 1 5 Xaal Xaa 2 Xaa 3 Gly Thr Xaa 4 Xaas Xaa 6 Xaa 7 Xaa 8 Ser Lys Gln Xaag Glu Glu Glu Ala Val Arg Leu Xaalo Xaanl Xaal2 Xaa 13 Leu Lys Asn Gly Gly Xaal4 Ser Ser Gly Ala Xaa 5 l Xaa 16 Xaal7 Xaalg-

Z

oo oboe wherein Xaa, is His, Arg or Tyr; Xaa 2 is Ser, Gly, Ala or Thr; Xaa 3 is Asp or Glu; Xaa 4 is Phe, Tyr or naphthylalanine; Xaa 5 is Thr or Ser; Xaa 6 is Ser or Thr; Xaa 7 is Asp or Glu; Xaa 8 is Leu, Ile, Val, pentylglycine or Met; Xaa 9 is Leu, Ile, pentylglycine, Val or Met; Xaalo is Phe, Tyr or naphthylalanine; Xaal, is Ile, Val, Leu, pentylglycine, tert-butylglycine or Met; Xaal2 is Glu or Asp; Xaa,3 is Trp, Phe, Tyr, or naphthylalanine; [R:\LIBZ\Vaughan\Prosecutions\452630DI ]452630D .RL2.consistories.doc:VNB -7b Xaa 1 4 Xaa 1 5 Xaa 1 6 and Xaa 1 7 are independently Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine or N-alkylalanine; Xaa 1 8 is Ser, Thr or Tyr; and Z is -OH or -NH 2 and pharmaceutically acceptable salts thereof, with the proviso that the compound does not have the formula of either exendin-3 [SEQ. ID. NO. 1] or exendin-4 [SEQ. ID. NO. and with the proviso that the exendin agonist is not glucagon-like peptide 1, and further that the exendin agonist is not an exendin analogue that consists of an exendin analog corresponding to positions 1-30, 2-30, or 3-30 of exendin 3 or exendin 4 unless the amino acid at position 30 is glycine; or consists of an exendin analog corresponding to positions 1-27, 1-28, 1-29, 2-27, 2-28, 2-29, 3-27, 3-28, or 3-29 of exendin 3 or exendin 4.

In yet another aspect, there is provided an exendin or exendin agonist when used in treating type 1 diabetes mellitus, wherein said exendin agonist is selected from a peptide compound of the formula: 9 9 .9.

0 .9 9 9 1 5 Xaaj Xaa 2 Xaa 3 Gly Thr Xaa 4 Xaa 5 Xaa 6 Xaa 7 Xaa 8 Ser Lys Gin Xaa 9 Glu Glu Glu Ala Val Arg Leu Xaalo Xaa 1 1 Xaa 1 2 Xaa 13 Leu Lys Asn Gly Gly Xaa 14 Ser Ser Gly Ala Xaa 15 Xaa 16 Xaa 17 Xaa 18 z 20 wherein Xaa 1 is His, Arg or Tyr; Xaa 2 is Ser, Gly, Ala or Thr; Xaa, is Asp or Glu; Xaa 4 is Phe, Tyr or naphthylalanine; Xaa 5 is Thr or Ser; Xaa 6 is Ser or Thr; Xaa 7 is Asp or Glu; [R:\LIBZ\Vaughan\Prosecutions\452630D I ]452630D I.RL2.consistoriesdoc:VNB -7c Xaa 8 is Leu, Ie, Val, pentyiglycine or Met; Xaa 9 is Leu, Ie, pentylglycine, Val or Met; Xaa 1 0 is Phe, Tyr or naphthylalanine; Xaa 11 is Ie, Val, Leu, pentyiglycine, tert-butyiglycine or Met; Xaa 1 2 is Glu or Asp; Xaa 1 3 is Trp, Phe, Tyr, or naphthylalanine; Xaa 1 4 Xaa 1 5 Xaa 1 6 and Xaa 1 7 are independently Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine or N-alkylalanine; Xaa 1 8 is Ser, Thr or Tyr; and Z is -OH or -NH 2 and pharmaceutically acceptable salts thereof, is with the proviso that the compound does not have the formula of either exendin-3 [SEQ. ID. NO. 1] or exendin-4 [SEQ. ID. NO. and with the proviso that the exendin agonist is not glucagon-like peptide 1, and further that the exendin agonist is not an exendin analog that consists of an exendin analog corresponding to positions 1-30, 2-30, or 3-30 of exendin 3 or exendin 4 unless the amino acid at position 30 is glycine; or consists of an 20 exendin analog corresponding to positions 1-27, 1-28, 1-29, 2-27, 2-28, 2-29, 3-27, 3-28, or 3-29 of exendin 3 or exendin 4.

In yet another aspect, there is provided the use of an exendin or exendin agonist in the preparation of a medicament for treating type 1 diabetes mellitus, wherein said exendin agonist is selected from a peptide compound of the formula: C 0

C

C

C

C

C..

C@

C

C

CC C 00

C

1 5 Xaa 1 Xaa 2 Xaa 3 Gly Thr Xaa 4 Xaa 5 Xaa 6 Xaa 7 Xaa 8 15 Ser Lys Gin Xaa 9 Glu Glu Glu Ala Val Arg Leu 125 130 Xaa 10 Xaall Xaa 12 Xaa 13 Leu Lys Asn Gly Gly Xaa 14 Ser Ser Gly Ala Xaa, 5 Xaa 16 Xaa 17 Xaa 18 I I_ z_ [R:\LIBZ\Vaughan\Prosecutians\452630D I ]452630D I.RL2.consistories.doc:VNB -7d wherein Xaa, is His, Arg or Tyr; Xaa 2 is Ser, Gly, Ala or Thr; Xaa 3 is Asp or Glu; Xaa 4 is Phe, Tyr or naphthylalanine; Xaa 5 is Thr or Ser; Xaa 6 is Ser or Thr; Xaa 7 is Asp or Glu; Xaa 8 is Leu, Ile, Val, pentylglycine or Met; Xaa 9 is Leu, Ile, pentylglycine, Val or Met; Xaao is Phe, Tyr or naphthylalanine; Xaal, is Ile, Val, Leu, pentylglycine, tert-butylglycine or Met; Xaal2 is Glu or Asp; Xaa 13 is Trp, Phe, Tyr, or naphthylalanine; Xaa,4, Xaal, Xaal6 and Xaa17 are independently Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine or N-alkylalanine; Xaa 8 is Ser, Thr or Tyr; and 20 Z is -OH or -NH 2 and pharmaceutically acceptable salts thereof, with the proviso that the compound does not have the formula of either exendin-3 [SEQ. ID. NO. 1] or exendin-4 [SEQ. ID. NO. and with the proviso that the exendin agonist is not glucagon-like peptide 1, and further that the exendin agonist is not an exendin S' 25 analog that consists of an exendin analog corresponding to positions 1-30, 2-30, or 3-30 o of exendin 3 or exendin 4 unless the amino acid at position 30 is glycine; or consists of an exendin analog corresponding to positions 1-27, 1-28, 1-29, 2-27, 2-28, 2-29, 3-27, 3-28, or 3-29 of exendin 3 or exendin 4.

In yet another aspect, there is provided a method of treating a disease or disorder 30 which may be benefited by a decrease in gastrointestinal motility or a delay in gastric emptying in a subject, the method comprising administering to the subject a therapeutically effective amount of an exendin or an exendin agonist that provides for the reduction in [R:\LIBZ\Vaughan\Prosecutions\452630DI ]452630DI.RL2.consistories.doc:VNB -7e gastric motility or delay in gastric emptying, wherein the disease or disorder is impaired glucose tolerance, with the proviso that the exendin agonist is not glucagon-like peptide 1.

In yet another aspect, there is provided an exendin or an exendin agonist when used for treating a disease or disorder which may be benefited by a decrease in gastrointestinal s motility or a delay in gastric emptying wherein the disease or disorder is impaired glucose tolerance, with the proviso that the exendin agonist is not glucagon-like peptide 1.

In yet another aspect, there is provided the use of an exendin or an exendin agonist in the manufacture of a medicament for treating a disease or disorder which may be benefited by a decrease in gastrointestinal motility or a delay in gastric emptying wherein the disease or 0o disorder is impaired glucose tolerance, with the proviso that the exendin agonist is not glucagon-like peptide 1.

In yet another aspect, there is provided a method of treatment for ingestion of a toxin in a subject, the method comprising: administering to the subject an amount of an exendin or an exendin agonist effective to prevent or reduce the passage of stomach contents to the intestines; and aspirating the contents of the stomach, with the proviso that the exendin agonist is not glucagon-like peptide 1.

In yet another aspect, there is provided a method of treatment for ingestion of a toxin, the method comprising: administering an amount of an exendin or an exendin agonist effective to prevent or reduce the passage of stomach contents to the intestines; and (b) 20 aspirating the contents of the stomach, wherein the exendin or the exendin agonist is substantially as hereinbefore described with reference to any one of Examples 4 to 35 and with the proviso that the exendin agonist is not glucagon-like peptide 1.

In yet another aspect, there is provided an exendin or an exendin agonist when used °for treatment for ingestion of a toxin with the proviso that the exendin agonist is not 25 glucagon-like peptide 1.

In yet another aspect, there is provided the use of an exendin or an exendin agonist in the manufacture of a medicament for treatment for ingestion of a toxin with the proviso that the exendin agonist is not glucagon-like peptide 1.

In yet another aspect, the invention is directed to a method of treating post-prandial hyperglycemia by administering to a subject a therapeutically effective amount of an exendin or exendin agonist, with the proviso that the exendin agonist is not glucago-like peptide 1. In a preferred embodiment, the post-prandial hyperglycemia is a consequence of Type 2 diabetes mellitus. In other preferred embodiments, the post-prandial hyperglycemia is a [R:\LIBZ\Vaughan\Prosecutions\452630DI ]452630Dl .RL2.consistories.doc:VNB -7fconsequence of Type 1 diabetes mellitus or impaired glucose tolerance. For the treatment of Type 1 diabetes mellitus in addition to not being glucagon-like peptide 1, the exendin agonist is not an exendin analogue that a) consists of an exendin analog corresponding to positions 1- 2-30, or 3-30 of exendin 3 or exendin 4 unless the amino acid at position 30 is glycine; or b) consists of an exendin analog corresponding to positions 1-27, 1-28, 1-29, 2-27, 2-28, 2- 29, 3-27, 3-28, or 3-29 of exendin 3 or exendin 4.

In another aspect, a therapeutically effective amount of an amylin agonist is also administered to the subject. In a preferred aspect, the amylin agonist is an amylin or ft* oo oo [R:\LIBZ\Vaughan\Prasecutions\452630D 1 ]452630D1.RL2.consistories.doc:VNB 8 an amylin agonist analog such as 2s 52 29 'Pro-human-amylin.

The use of amylin agonists to treat post-prandial hyperglycemia, as well as to beneficially regulate gastrointestinal motility, is described in International Application No. PCT/US94/10225, published March 16, 1995 which has been incorporated by reference herein.

In yet another aspect, a therapeutically effective amount of an insulin or insulin analog is also administered, separately or together with an exendin or exendin agonist, to the subject.

In another aspect, the invention is directed to a method of treating ingestion of a toxin by administering an amount of an exendin or an exendin agonist effective to Sprevent or reduce passage of stomach contents to the intestines and aspirating the stomach contents.

lefinitions In accordance with the present invention and as used herein, the following terms are defined to have the following meanings, unless explicitly stated otherwise.

The term "amino acid" refers to natural amino acids, unnatural amino acids, and amino acid analogs, all in their D and L stereoisomers if their structure allow such stereoisomeric forms. Natural amino acids include alanine (Ala), arginine (Arg), asparagine (Asn), aspartic acid (Asp), cysteine (Cys), glutamine (Gln), glutamic acid (Glu), glycine (Gly), histidine (His), isoleucine (Ile), leucine (Leu), Lysine (Lys), methionine (Met), phenylalanine (Phe), proline (Pro), serine (Ser), threonine (Thr), typtophan (Trp), tyrosine (Tyr) and valine (Val). Unnatural amino acids include, but are not limited to azetidinecarboxylic acid, 2-aminoadipic acid, 9 3-aminoadipic acid, beta-alanine, aminopropionic acid, 2aminobutyric acid, 4-aminobutyric acid, 6-aminocaproic acid, 2-aminoheptanoic acid, 2-aminoisobutyric acid, 3aminoisbutyric acid, 2-aminopimelic acid, tertiarybutylglycine, 2,4-diaminoisobutyric acid, desmosine, 2,2'diaminopimelic acid, 2,3-diaminopropionic acid,

N-

ethylglycine, N-ethylasparagine, homoproline, hydroxylysine, allo-hydroxylysine, 3-hydroxyproline, 4hydroxyproline, isodesmosine, allo-isoleucine,

N-

methylalanine, N-methylglycine, N-methylisoleucine,

N-

methylpentylglycine, N-methylvaline, naphthalanine, norvaline, norleucine, ornithine, pentylglycine, pipecolic acid and thioproline. Amino acid analogs include the ceial natural and unnatural amino acids which are chemically blocked, reversibly or irreversibly, or modified on their N-terminal amino group or their side-chain groups, as for example, methionine sulfoxide, methionine sulfone,

S-

(carboxymethyl)-cysteine, S-(carboxymethyl)-cysteine sulfoxide and S-(carboxymethyl)-cysteine sulfone.

20 The term "amino acid analog" refers to an amino acid wherein either the C-terminal carboxy group, the Nterminal amino group or side-chain functional group has been chemically codified to another functional group. For example, aspartic acid-(beta-methyl ester) is an amino acid analog of aspartic acid; N-ethylglycine is an amino acid analog of glycine; or alanine carboxamide is an amino acid analog of alanine.

The term "amino acid residue" refers to radicals having the structure: wherein R typically is wherein R' is an amino acid side chain, typically H or a carbon containing substitutent;

(CH

2

)P

or wherein p is 1, 2 or 3 representing the azetidinecarboxylic acid, proline or pipecolic acid residues, respectively.

The term "lower" referred to herein in connection with organic radicals such as alkyl groups defines such groups with up to and including about 6, preferably up to and including 4 and advantageously one or two carbon atoms. Such groups may be straight chain or branched chain.

"Pharmaceutically acceptable salt" includes salts of the compounds of the present invention derived from the S: combination of such compounds and an organic or inorganic acid. In practice the use of the salt form amounts to use of the base form. The compounds of the present invention 15 are useful in both free base and salt form, with both forms being considered as being within the scope of the present invention.

In addition, the following abbreviations stand for the following: 20 "ACN" or "CHCN" refers to acetonitrile.

"Boc", "tBoc" or "Tboc" refers to t-butoxy carbonyl.

"DCC" refers to N,N'-dicyclohexylcarbodiimide.

"Fmoc" refers to fluorenylmethoxycarbonyl.

"HBTU" refers to 2-(1H-benzotriazol-l-yl)- 1,1,3,3,-tetramethyluronium hexaflurophosphate.

"HOBt" refers to l-hydroxybenzotriazole monohydrate.

"homoP" or hPro" refers to homoproline.

"MeAla" or "Nme" refers to N-methylalanine.

"naph" refers to naphthylalanine.

"pG" or pGl"y" refers to pentylglycine.

"tBuG" refers to tertiary-butylglycine.

"ThioP" or tPro" refers to thioproline.

BRIEF DESCRIPTION OF THE DRAWINGS FIGURE 1 shows a comparison of the amino acid sequences of exendin 3, exendin 4, and exendin[9-39] using standard single letter rather than three letter amino acid codes.

FIGURE 2 shows GLP-1[7-36]NH,, exendin-3 and exendin-4 dose-response effects of prior subcutaneous injection on the retention of gastric contents 20 minutes after gavage in normal rats (n 3-17 for each point). Symbols are means A SEM and the curves define the best fitting logistic functions. "Zero" indicates the fraction of gastric contents retained in untreated normal rats.

FIGURE 3 shows the dose response effects of prior injection of exendin-4 (n 29), exendin-4 acid (n 36) 15 and "Leu, 2 Phe exendin-4 (n 36) on the retention of gastric contents 20 minutes after gavage in normal rats.

Symbols are means plus or minus standard error of the mean and the curves define the best fitting logistic functions.

"Zero" indicates the fraction of gastric contents retained 20 in untreated normal rats.

FIGURE 4 shows the effect of prior injection of g exendin-4 n=6; 1.0 Ag exendin-4 (sc) plus 0.3 mg exendin[9-39] n=6; and 0.3 mg exendin[9-39] (sc), n=6 on the retention of gastric contents 20 minutes after 25 gavage. Also shown are saline controls at t=0 and min. The error bars show standard error of the mean. As shown in FIGURE 4, exendin-4 alone potently inhibited gastric emptying. Exendin[9-39] (sc) alone had no effect on gastric emptying. When injected along with exendin-4, exendin[9-39] did not antagonize the effect of exendin-4 on gastric emptying inhibition.

FIGURE 5 shows the effect of prior injection of 0.3 Lig exendin-4 n=5 and 0.3 pg exendin-4 (sc) plus mg exendin[9-39] n=5 on the retention of gastric contents 20 minutes after gavage. Also shown are saline controls at t+0 and t=20 min. The error bars- show standard error of the mean. As shown in FIGURE exendin-4 alone potently inhibited gastric emptying. When injected along with exendin-4, exendin[9-39] (iv) did not antagonize the effect of exendin-4 on gastric emptying inhibition.

FIGURE 6 shows the effect of prior injection of 10 ig GLP-1[7-36]NH, n=8; 10 ~g GLP-1[7-36]NH, (sc) plus 3 mg exendin[9-39] n=6; and 0.3 mg exendin[9-39] (sc), n=6 on the retention of gastric contents 20 minutes after 15 gavage. Also shown are saline controls at t=0 and Smin. The error bars show standard error of the mean. As shown in FIGURE 6, GLP-1]7-36]NH 2 potently inhibited gastric emptying. Exendin[9-39] (sc) alone had no effect on gastric emptying. When injected along with GLP-1[7- 20 36]NH 2 exendin[9-39] did not antagonize the effect of GLP- 1[7-36]NH 2 on gastric emptying inhibition.

FIGURE 7 shows the effect of prior injection of 10 kg GLP-1[7-36]NH 2 n=8, and 10 Mg GLP-1[7-36]N1 (sc) plus 0.5 mg exendin[9-39] n=3 on the retention of 25 gastric contents 20 minutes after gavage. Also shown are *saline controls at t=0 and t=20 min. The error bars show standard error of the mean. As shown in FIGURE 7, GLP- 1[7-36]NH, alone potently inhibited gastric emptying. When injected along with GLP-1[7-36N1h, exendin[9-39] (iv) did not antagonize the effect of GLP-1[7-36]NH, on gastric emptying inhibition.

FIGURE 8-1 and 8-2 depicts the amino acid sequences for certain exendin agonists [SEQ. ID. NOS. 5 TO DETAT.ED DESCRTPTTON OF THE INVENTION Exendins and exendin agonists (including exendin analogs and exendin derivatives) are useful in this invention in view of their pharmacological properties.

Activity as exendin agonists can be indicated by activity in the assays described below. Effects of exendins or exendin agonists on gastric motility and gastric emptying can be identified, evaluated, or screened for, using the methods described in Examples 1-3 below, or other artknown or equivalent methods for determining gastric motility. Negative receptor assays or screens for exendin agonist compounds or candidate exendin agonist compounds, 15 such as a GLP-1 receptor preparation, an amylin receptor assay/screen using an amylin receptor preparation as described in U.S. Patent No. 5,264,372, issued November 23, 1993, the contents of which are incorporated herein by reference, one or more calcitonin receptor assays/screens using, for example, T47D and MCF7 breast carcinoma cells, which contain calcium receptors coupled to the stimulation of adenyl cyclase activity, and/or a CGRP receptor assay/screen using, for example, SK-N-MC cells, can be used to evaluate and/or confirm exendin agonist activity.

One such method for use in identifying or evaluating the ability of a compound to slow gastric motility, comprises: bringing together a test sample and a test system, said test sample comprising one or more test compounds, said test system comprising a system for evaluating gastric motility, said system being characterized in that it exhibits, for example, elevated plasma glucose in response to the introduction to said system of glucose or a meal; and, determining the presence or amount of a rise in plasma glucose in said system. Positive and/or negative controls may be used as well.

Exendins and exendin agonist compounds such as exendin analogs and exendin derivatives, described herein may be prepared through peptide purification as described in, for example, Eng, et al., J. Biol Chem. 265:20259-62, 1990; and Eng, et al., J. Biol. Chem. 267:7402-05, 1992, hereby incorporated by reference herein. Alternatively, exendins and exendin agonist peptides may be prepared by methods known to those skilled in the art, for example, as described in Raufman, et al. LJ- Biol. Chem. 267:21432-37, 15 1992), hereby incorporated by reference herein, using standard solid-phase peptide synthesis techniques and preferably an automated or semiautomated peptide synthesizer. Typically, an a-N-carbamoyl protected amino acid and an amino acid attached to the growing peptide 20 chain on a resin are coupled at room temperature in an inert solvent such as dimethylformamide, N-methylpyrrolidinone or methylene chloride in the presence of coupling agents such as dicyclohexylcarbodiimide and 1-hydroxybenzotriazole in the presence of a base such as diisopropylethylamine. The a-N-carbamoyl protecting group is removed from the resulting peptide-resin using a reagent such as trifluoroacetic acid or piperidine, and the coupling reaction repeated with the next desired N-protected amino acid to be added to the peptide chain. Suitable N-protecting groups are well known in the art, with t-butyloxycarbonyl (tBoc) and fluorenylmethoxycarbonyl (Fmoc) being preferred herein.

The solvents, amino acid derivatives and 4-methylbenzhydryl-amine resin used in the peptide synthesizer may be purchased from Applied Biosystems Inc.

(Foster City, CA). The side-chain protected amino acids, such as Boc-Arg(Mts), Fmoc-Arg(Pmc), Boc-Thr(Bzl), Fmoc-Thr(t-Bu), Boc-Ser(Bzl), Fmoc-Ser(t-Bu), Boc-Tyr(BrZ), Fmoc-Tyr(t-Bu), Boc-Lys(Cl-Z), Fmoc-Lys(Boc), Boc-Glu(Bzl), Fmoc-Glu(t-Bu), Fmoc-His(Trt), Fmoc-Asn(Trt), and Fmoc-Gln(Trt) may be purchased from Applied Biosystems, Inc. Boc-His(BOM) may be purchased from Applied Biosystems, Inc. or Bachem Inc.

(Torrance, CA). Anisole, methylsulfide, phenol, .ethanedithiol, and thioanisole may be obtained from 15 Aldrich Chemical Company (Milwaukee, WI). Air Products and Chemicals (Allentown, PA) supplies HF. Ethyl ether, acetic acid and methanol may be purchased from Fisher Scientific (Pittsburgh, PA).

Solid phase peptide synthesis may be carried out with 20 an automatic peptide synthesizer (Model 430A, Applied Biosystems Inc., Foster City, CA) using the NMP/HOBt (Option 1) system and tBoc or Fmoc chemistry (see, Applied Biosystems User's Manual for the ABI 430A Peptide 2 Synthesizer, Version 1.3B July 1, 1988, section 6, pp.

o. 25 49-70, Applied Biosystems, Inc., Foster City, CA) with capping. Boc-peptide-resins may be cleaved with HF to 0 C, 1 hour). The peptide may be extracted from the resin with alternating water and acetic acid, and the filtrates lyophilized. The Fmoc-peptide resins may be cleaved according to standard methods (Introduction to Cleavage Techniques, Applied Biosystems, Inc., 1990, pp.

6-12). Peptides may be also assembled using an Advanced Chem Tech Synthesizer (Model MPS 350, Louisville, Kentucky). Peptides may be purified by RP-HPLC (preparative and analytical) using a Waters Delta Prep 3000 system. A C4, C8 or C18 preparative column (10 y, 2.2 x 25 cm; Vydac, Hesperia, CA may be used to isolate peptides, and purity may be determined using a C4, C8 or C18 analytical column (5 p, 0.46 x 25 cm; Vydac).

Solvents TFA/water and B=0.1% TFA/CH 3 CN) may be delivered to the analytical column at a flowrate of ml/min and to the preparative column at 15 ml/min. Amino acid analyses may be performed on the Waters Pico Tag system and processed using the Maxima program. The peptides may be hydrolyzed by vapor-phase acid hydrolysis (115 0 C, 20-24 Hydrolysates may be derivatized and 15 analyzed by standard methods (Cohen, Meys, and Tarrin, T.L. (1989), The Pico Tag Method: A Manual of Advanced Techniques for Amino Acid Analysis, pp. 11-52, Millipore Corporation, Milford, MA). Fast atom bombardment analysis may be carried out by M-Scan, 20 Incorporated (West Chester, PA). Mass calibration may be performed using cesium iodide or cesium iodide/glycerol.

Plasma desorption ionization analysis using time of flight detection may be carried out on an Applied Biosystems Bio-Ion 20 mass spectrometer.

25 Peptide compounds useful in the invention may also be prepared using recombinant DNA techniques, using methods now known in the art. See, Sambrook, et al., Molecular Cloning: A Laboratory Manual, 2d Ed., Cold Spring Harbor (1989). Alternatively, such compounds may be prepared by homogeneous phase peptide synthesis methods.

The use of exendin analogs or derivatives is included within the methods of the present invention. Exendin analogs or derivatives are functional variants having similar amino acid sequence and retaining, to some extent, at least the gastric motility- and gastric emptyingrelated activities of the related exendin. By "functional variant" is meant an analog or derivative which has an activity that can be substituted for one or more activities of a particular exendin. Preferred functional variants retain all of the activities of a particular exendin, however, the functional variant may have an activity that, when measured quantitatively, is stronger or weaker, as measured in exendin functional assays, for example, such as those disclosed herein. Preferred .0 15 functional variants have activities that are within about 1% to about 10,000% of the activity of the related exendin, more preferably between about 10% to about 1000%, and more preferably within about 50% to about 500%.

Derivatives have at least about 15% sequence similarity, 20 preferably about 70%, more preferably about 90%, and even more preferably about 95% sequence similarity to the Ooo related exendin. "Sequence similarity" refers to "homology" observed between amino acid sequences in two different polypeptides, irrespective of polypeptide 25 origin.

The ability of the analog or derivative to retain some activity can be measured using techniques described herein.

Derivatives include modification occurring during or after translation, for example, by phosphorylation, glycosylation, crosslinking, acylation, proteolytic cleavage, linkage to an antibody molecule, membrane molecule or other ligand (see Ferguson et al., Annu Rev Binhem. 57:285-320, 1988) Specific types of analogs include amino acid alterations such as deletions, substitutions, additions, and amino acid modifications. A "deletion" refers to the absence of one or more amino acid residue(s) in the related polypeptide. An "addition" refers to the presence of one or more amino acid residue(s) in the related polypeptide. Additions and deletions to a polypeptide may be at the amino terminus, the carboxy terminus, and/or internal. Amino acid "modification" refers to the alteration of a naturally occurring amino acid to produce a non-naturally occurring amino acid. A "substitution" refers to the replacement of one or more amino acid 15 residue(s) by another amino acid residue(s) in the .polypeptide. Analogs can contain different combinations of alterations including more than one alteration and different types of alterations.

Preferred analogs have one or more amino acid 20 alteration(s) which do not significantly affect exendin S"agonist activity. In regions of the exendin not necessary for exendin agonist activity, amino acids may be deleted, added or substituted with less risk of affecting activity.

In regions required for exendin agonist activity, amino acid alterations are less preferred as there is a greater risk of affecting exendin activity. Such alterations should be conservative alterations. For example, one or more amino acid residues within the sequence can be substituted by another amino acid of a similar polarity which acts as a functional variant.

Conserved regions tend to be more important for protein activity than non-conserved regions. Known 19 procedures may be used to determine the conserved and nonconserved regions important of receptor activity using in vitro mutagenesis techniques or deletion analyses and measuring receptor activity as described by the present disclosure.

Modifications to a specific polypeptide may be deliberate, as through site-directed mutagenesis and amino acid substitution during solid-phase synthesis, or may be accidental such as through mutations in hosts or systems which produce the polypeptide.

Compounds particularly useful according to the present invention are exendin agonist compounds of the formula [SEQ. ID. NO. 4]: 1 5 15 Xaa 1 Xaa, Xaa 3 Gly Thr Xaa 4 Xaa s Xaa 6 Xaa, Xaa, 15 Ser Lys Gln Xaa, Glu Glu Glu Ala Val Arg Leu 25 Xaa 0 Xaa,, Xaa2 Xaa 3 Leu Lys Asn Gly Gly Xaa,, Ser Ser Gly Ala Xaas, Xaa 1 Xaa,, Xaa,,-Z wherein Xaa, is His, Arg or Tyr; Xaa 2 is Ser, Gly, Ala or Thr; Xaa 3 is Asp or GlIu; Xaa is Phe, Tyr or naphthalanine;Xaa 5 is Thr or Ser; Xaa 6 is Ser or Thr; Xaa, is Asp or Glu; Xaa, is Leu, Ile, Val, pentylglycine or Met; Xaa, is Leu, Ile, pentylglycine, Val or Met; Xaa, 0 is Phe, Tyr or naphthalanine; Xaajn is Ile, Val, Leu, pentylglycine, tert-butylglycine or Met; Xaaj 2 is Glu or Asp; Xaa 13 is Trp, Phe, Tyr, or naphthylalanine; Xaa Xaa 15 Xaa 6 and Xaq, are independently Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, Nalkylpentylglycine or N-alkylalanine; Xaa,, is Ser, Thr or Tyr; and Z is -OH or with the proviso that the compound does not have the formula of either SEQ. ID. NOS.

1 or 2. Preferred N-alky! groups for N-alkylglycine, Nalkylpentylglycine and N-alkylalanine include lower alkyl groups preferably of 1 to about 6 carbon atoms, more preferably of 1 to 4 carbon atoms. Suitable compounds include those having amino acid sequences of SEQ. ID. NOS.

to Preferred exendin agonist compounds include those wherein Xaa, is His or Tyr. More preferably Xaa, is His.

Preferred are those compounds wherein Xaa 2 is Gly.

Preferred are those compounds wherein Xaa, is Leu, pentylglycine or Met.

Preferred compounds include those wherein Xaa 3 is Trp or Phe.

15 Also preferred are compounds where Xaa 4 is Phe or naphthalanine; Xaa,, is Ile or Val and Xaa Xaa Xaa 1 and Xaa,, are independently selected from Pro, homoproline, thioproline or N-alkylalanine. Preferably N-alkylalanine has a N-alkyl group of 1 to about 6 carbon atoms.

20 According to an especially preferred aspect, Xaa 15 Xaa 16 and Xaa 1 are the same amino acid reside.

Preferred are compounds wherein Xaaj, is Ser or Tyr, more preferably Ser.

Preferably Z is -NH,.

25 According to one aspect, preferred are compounds of formula wherein Xaa, is His or Tyr, more preferably His; Xaa 2 is Gly; Xaa 4 is Phe or naphthalanine; Xaa, is Leu, pentylglycine or Met; Xaao, is Phe or naphthalanine; Xaa 1 is Ile or Val; Xaa,,, Xaa,,, Xaa,, and Xaa, are independently selected from Pro, homoproline, thioproline or Nalkylalanine; and Xaa,, is Ser or Tyr, more preferably Ser.

More preferably Z is -NH,.

According to an especially preferred aspect, especially preferred compounds include those of formula wherein: Xaa, is His or Arg; Xaa, is Gly; Xaa 3 is Asp or Glu; Xaa 4 is Phe or napthylalanine; Xaa 5 is Thr or Ser; Xaa 6 is Ser or Thr; Xaa, is Asp or Glu; Xaa is Let or pentylglycine; Xaa, is Leu or pentylglycine; Xaz 0 is Phe or naphthylalanine; Xaa 2 is Ile, Val or t-butyltylglycine; Xaa 2 is Glu or Asp; Xaa, 3 is Trp or Phe; Xaa 14 Xaas, Xa 6 and Xaa are independently Pro, homoproline, thioproline, or N-methylalanine; Xaae, is Ser or Tyr: and Z is -OH or with the proviso that the compound does not have the formula of either SEQ. ID. NOS.

1 or 2. More preferably Z is Especially preferred compounds include those having the amino acid sequence of 15 SEQ. ID. NOS. 5, 6, 17, 18, 19, 22, 24, 31, 32 and According to an especially preferred aspect, provided are compounds where Xaa, is Leu, Ile, Val or pentylglycine, more preferably Leu or pentylglycine, and Xaa 13 is Phe, Tyr or naphthylalanine, more preferably Phe or 20 naphthylalanine. These compounds are believed to exhibit advantageous duration of action and to be less subject to oxidative degration, both in vitro and in vivo, as well as during synthesis of the compound.

S* The compounds referenced above form salts with 25 various inorganic and organic acids and bases. Such salts include salts prepared with organic and inorganic acids, for example, HC1, HBr, HSO,, H 3 PO,, trifluoroacetic acid, acetic acid, formic acid, methanesulfonic acid, toluenesulfonic acid, maleic acid, fumaric acid and camphorsulfonic acid. Salts prepared with bases include ammonium salts, alkali metal salts, e.g. sodium and potassium salts, and alkali earth salts, e.g. calcium and magnesium salts. Acetate, hydrochloride, and trifluoroacetate salts are preferred. The salts may be formed by conventional means, as by reacting the free acid or base forms of the product with one or more equivalents of the appropriate base or acid in a solvent or medium-in which the salt is insoluble, or in a solvent such as water which is then removed in vacuo or by freeze-drying or by exchanging the ions of an existing salt for another ion on a suitable ion exchange resin.

The compounds referenced above form salts with various inorganic and organic acids and bases. Such salts include salts prepared with organic and inorganic acids, for example, HCI, HBr, H 2

S

4

H

3

P

4 trifluoroacetic acid, acetic acid, formic acid, methanesulfonic acid, 15 toluenesulfonic acid, maleic acid, fumaric acid and camphorsuilfonic acid. Salts prepared with bases include ammonium salts, alkali metal salts, e.g. sodium and potassium salts, and alkali earth salts, e.g. calcium and magnesium salts. Acetate, hydrochloride, and trifluoroacetate salts are preferred. The salts may be formed by conventional means, as by reacting the free acid or base forms of the product with one or more equivalents of the appropriate base or acid in a solvent or medium in o o S"which the salt is insoluble, or in a solvent such as water which is then removed in vacuo or by freeze-drying or by exchanging the ions of an existing salt for another ion on a suitable ion exchange resin.

The compounds described above are useful in view of their pharmacological properties. In particular, the compounds of the invention possess activity as agents to regulate gastric motility and to slow gastric emptying, as evidenced by the ability to inhibit gastric emptying levels in mammals.

As described in Example 1, gastric emptying was measured in normal Sprague Dawley rats using the retention of an acaloric methylcellulose gel containing Phenol Red delivered by gavage. Dye content in stomachs removed after sacrifice 20 minutes later was determined spectroscopically, and was compared to that in rats sacrificed immediately after gavage to assess emptying.

The exendins, exendin 3 and exendin 4, dose-dependently inhibited gastric emptying. The EDso of the response to exendin 3 and exendin 4 was 0.1 and 0.08 pg, respectively, demonstrating that the exendins were -170-290 times more potent than GLP-1(7-36]NH, in inhibiting gastric emptying.

As described in Example 2, the effects of exendin-4 15 and the exendin-4 analogs, exendin-4 acid and 1 Leu, 2 Phe exendin-4, on inhibition of gastric emptying were examined. Exendin-4 and the exendin-4 analogs dose dependently inhibiting gastric emptying. The EDso of exendin-4 was 0.27 pg. The EDs 0 s of exendin-4 acid and 20 1 Leu, 2 sPhe exendin-4 were 0.12 ig and 0.29 pg, respectively, indicating that the potency of the analogs was comparable to that of exendin-4.

As described in Example 3, the effects of exendin-4 and the cloned GLP-1 receptor antagonist, 25 exendin[9-39] on gastric emptying were examined. After minutes, the animals treated with exendin-4 showed potent inhibition of gastric emptying, which was not reversed by exendin[9-39]. This occurred regardless of whether the exendin[9-39] was administered sc or iv. Exendin[9-39] alone had no effect on gastric emptying.

As noted above, exendin[9-39] is a potent antagonist of GLP-1 which binds at the cloned GLP-1 receptor (Fehmann HC, et al., Eeptides 15(3): 453-6, 1994; Thorens B, et al., Di~behtr 42(11): 1678-82, 1993).

Surprisingly, however, exendin[9-39] did not block the effect of exendin-4 on gastric emptying (see Figures 4 and These results indicate that the effects of exendins and exendin agonists on gastric emptying are not due binding of the exendins at the cloned GLP-1 receptor, but instead that the gastric emptying effects of exendins and exendin agonists are due to their action on a separate receptor.

That exendins can act via mechanisms other than those attributable to the cloned GLP-1 receptor is further evidenced by the reported absence of effect of exendin-4 on inhibition of pentagastrin-induced gastric acid 15 secretion, despite the inhibitory effect of GLP-1 on such secretion. Gedulin, et al., Diabetologia, 1):A300 (Abstract 1181) (1997). Additionally, as described in commonly assigned U.S. Provisional Patent Application Serial No. 60/034,905, entitled, "Use of 20 Exendins and Agonists Therefor for the Reduction of Food Intake," filed January 7, 1997, peripherally injected exendin inhibited food intake in mice, an action not S- observed with GLP-1.

Compositions useful in the invention may conveniently be provided in the form of formulations suitable for parenteral (including intravenous, intramuscular and subcutaneous) or nasal or oral administration. In some cases, it will be convenient to provide an exendin or exendin agonist and another anti-emptying agent, such as glucagon, or amylin, or an amylin agonist, in a single composition or solution for administration together. In other cases, it may be more advantageous to administer another anti-emptying agent separately from said exendin or exendin agonist. A suitable administration format may best be determined by a medical practitioner for each patient individually. Suitable pharmaceutically acceptable carriers and their formulation are described in standard formulation treatises, Remington's Pharmaceutical Sciences by E.W. Martin. See also Wang, Y.J. and Hanson, M.A. "Parenteral Formulations of Proteins and Peptides: Stability and Stabilizers," Journal of Parenteral Science and Technology, Technical Report No.

Supp. 42:2S (1988).

Compounds useful in the invention can be provided as parenteral compositions for injection or infusion. They can, for example, be suspended in an inert oil, suitably 15 a vegetable oil such as sesame, peanut, olive oil, or other acceptable carrier. Preferably, they are suspended in an aqueous carrier, for example, in an isotonic buffer solution at a pH of about 5.6 to 7.4. These compositions may be sterilized by conventional sterilization 20 techniques, or may be sterile filtered. The compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions, such as pH buffering agents. Useful buffers include for example, sodium acetate/acetic acid buffers.

A form of repository or "depot" slow release preparation may be used so that therapeutically effective amounts of the preparation are delivered into the bloodstream over many hours or days following transdermal injection or delivery.

The desired isotonicity may be accomplished using sodium chloride or other pharmaceutically acceptable agents such as dextrose, boric acid, sodium tartrate, propylene glycol, polyols (such as mannitol and sorbitol), or other inorganic or organic solutes. Sodium chloride is preferred particularly for buffers containing sodium ions.

The claimed compositions can also be formulated as pharmaceutically acceptable salts acid addition salts) and/or complexes thereof. Pharmaceutically acceptable salts are non-toxic salts at the concentration at which they are administered. The preparation of such salts can facilitate the pharmacological use by altering the physical-chemical characteristics of the composition without preventing the composition from exerting its physiological effect. Examples of useful alterations in physical properties include lowering the melting point to facilitate transmucosal administration and increasing the 15 solubility to facilitate the administration of higher concentrations of the drug.

Pharmaceutically acceptable salts include acid addition salts such as those containing sulfate, hydrochloride, phosphate, sulfamate, acetate, citrate, 20 lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate. Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesu- Ifonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, and quinic acid. Such salts may be prepared by, for example, reacting the free acid or base forms of the product with one or more equivalents of the appropriate base or acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is then removed in vacuo or by freeze-drying or by exchanging the ions of an existing salt for another ion on a suitable ion exchange resin.

Carriers or excipients can also be used to facilitate administration of the compound. Examples of carriers and excipients include calcium carbonate, calcium phosphate, various sugars such as lactose, glucose, or sucrose, or types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols and physiologically compatible solvents. The compositions or pharmaceutical composition S 0 can be administered by different routes including intravenously, intraperitoneal, subcutaneous, and intramuscular, orally, topically, or transmucosally.

If desired, solutions of the above compositions may be thickened with a thickening agent such as methyl cellulose. They may be prepared in emulsified form, either water in oil or oil in water. Any of a wide variety of pharmaceutically acceptable emulsifying agents may be employed including, for example, acacia powder, a non-ionic surfactant (such as a Tween), or an ionic surfactant (such as alkali polyether alcohol sulfates or sulfonates, a Triton).

Compositions useful in the invention are prepared by mixing the ingredients following generally accepted procedures. For example, the selected components may be 25 simply mixed in a blender or other standard device to produce a concentrated mixture which may then be adjusted to the final concentration and viscosity by the addition of water or thickening agent and possibly a buffer to control pH or an additional solute to control tonicity.

For use by the physician, the compositions will be provided in dosage unit form containing an amount of an exendin or exendin agonist, for example, exendin 3.

exendin 4, with or without another antiemptying agent.

Therapeutically effective amounts of an exendin or exendin agonist for use in the control of gastric emptying and in conditions in which gastric emptying is beneficially slowed or regulated are those that decrease post-prandi-al blood glucose levels, preferably to no more than about 8 or 9 mM or such that blood glucose levels are reduced as desired. In diabetic or glucose intolerant individuals, plasma glucose levels are higher than in normal individuals. In such individuals, beneficial reduction or "smoothing" of post-prandial blood glucose levels, may be obtained. As will be recognized by those in the field, an effective amount of therapeutic agent will vary with many factors including the age and weight of the patient, the patient's physical condition, the blood sugar level or level of inhibition of gastric emptying to be obtained, and other factors.

Such pharmaceutical compositions are useful in causing gastric hypomotility in a subject and may be used 20 as well in other disorders where gastric motility is beneficially reduced.

The effective daily anti-emptying dose of the compounds will typically be in the range of 0.001 or 0.003 to about 5 mg/day, preferably about 0.001 or 0.05 to 2 mg/day and more preferably about 0.001 or 0.01 to 1 mg/day, for a 70 kg patient, administered in a single or divided doses. The exact dose to be administered is determined by the attending clinician and is dependent upon where the particular compound lies within the above quoted range, as well as upon the age, weight and condition of the individual. Administration should begin at the first sign of symptoms or shortly after diagnosis of diabetes mellitus. Administration may be by injection, preferably subcutaneous or intramuscular. Orally active compounds may be taken orally, however dosages should be increased 5-10 fold.

Generally, in treating or preventing elevated, inappropriate, or undesired post-prandial blood glucose levels, the compounds of this invention may be administered to patients in need of such treatment in a dosage ranges similar to those given above, however, the compounds are administered more frequently, for example, one, two, or three times a day.

The optimal formulation and mode of administration of compounds of the present application to a patient depend on factors known in the art such as the particular disease 15 or disorder, the desired effect, and the type of patient.

While the compounds will typically be used to treat human patients, they may also be used to treat similar or identical diseases in other vertebrates such as other primates, farm animals such as swine, cattle and poultry, and sports animals and pets such as horses, dogs and cats.

To assist in understanding the present invention, the following Examples are included. The experiments relating to this invention should not, of course, be construed as S" specifically limiting the invention and such variations of the invention, now known or later developed, which would be within the purview of one skilled in the art are considered to fall within the scope of the invention as described herein and hereinafter claimed.

EXAMPLE 1 The following study was carried out to examine the effects of exendin-3 and exendin-4 on gastric emptyin and to compare the effects with GLP-1[7-36]NH 2 treatment in rats. This experiment followed a modification of the method of Scarpignato, et al., Arch. Int. Pharmacodyn.

Ther. 246:286-94 (1980).

Male Harlan Sprague Dawley (HSD) rats were used. All animals were housed at 22.7±0.8 C in a 12:12 hour light:dark cycle (experiments being performed during the light cycle) and were fed and watered ad libitum (Diet LM-485, Teklad, Madison, WI). Exendin-3 and exendin-4 were synthesized according to standard peptide synthesis methods.

The determination of gastric emptying by the method described below was performed after a fast of -20 hours to ensure that the stomach contained no chyme that would 15 interfere with spectrophotometric absorbance measurements.

Conscious rats received by gavage, 1.5ml of an acaloric gel containing 1.5% methyl cellulose (M-0262, Sigma Chemical Co, St Louis, MO) and 0.05% phenol red indicator. Twenty minutes after gavage, rats were 20 anesthetized using 5% halothane, the stomach exposed and clamped at the pyloric and lower esophageal sphincters using artery forceps, removed and opened into an alkaline solution which was made up to a fixed volume. Stomach content was derived from the intensity of the phenol red in the alkaline solution, measured by absorbance at a wavelength of 560 nm. In separate experiments on 7 rats, the stomach and small intestine were both excised and opened into an alkaline solution. The quantity of phenol red that could be recovered from the upper gastrointestinal tract within 20 minutes of gavage was 89±4%; dye which appeared to bind irrecoverably to the gut luminal surface may have accounted for the balance. To 31 account for a maximal dye recovery of less than 100%, percent of stomach contents remaining after 20 min were expressed as a fraction of the gastric contents recovered from control rats sacrificed immediately after gavage in the same experiment. Percent gastric contents remaining (absorbance at 20 min)/(absorbance at 0 mm) x 100.

In baseline studies, with no drug treatment, gastric emptying over 20 min was determined. In dose-response studies, rats were treated with 0, 0.01, 0.1, 0.3, 1, 10, or 100 pg of exendin 3, exendin 4, or GLP-1(7-36)NH.

The results are shown in Figure 2. Figure 2 shows that exendins 3 and 4 inhibited gastric emptying with approximately the same ED 50 of 0.1 jg, whereas GLP-1(7-36)NH, has an ED 50 of approximately 9 jg, indicating that the exendins are -90 fold more potent than GLP-1 at inhibiting gastric emptying.

As shown in Table I, exendin-3 and exendin-4 were found to be potent inhibitors of gastric emptying. The effect of rat amylin on gastric emptying is also provided 20 as a second positive control and for comparitive purposes.

TABLE I r DOSE pg GLP-1 (7 36)NH, Excodin) Ezcndin-4 Rat Amyln remaining SEM remaining SEM rcmaining SEM rnmaining SEM Saine 4L0 (16) 3.50 46.760(1) 2.0 ".000 (17) 2.000 440 (17) 3.o Control 0.010 nodata 5.240 3.180 no data 2.000 37.60(2) 2.50 0.100 42.00 650 .770 500 72.00 12.000 2.70(6) 6.30 0.300 29.60 3.0 86.420 6.160 98.000 4.000 8820 3.00 1.000 37.20 2.70 95.330(3) 0.790 105.000 0.000 96.0 2.80 3.000 56.6 (10) .10 108.00(4) 2.70 87.90(11) 2.70 101.760(3) 3.90 112.000 2.000 101.10(6) 3.60 oo00.000 103.60 2.80 103.640 2.260 103.000(3) 3.000 101.20 *percent of gasric contnts ramining 20 minutes after gavag.

EXAMPLE 2 The effects of exendin-4 analogs on inhibition of gastric emptying were examined, and compared to the effects of exendin-4, according to the methods described in Example 1. Male HSD rats were treated with 0.01, 0.1, 0.3, 1, 10 and 100 pg of exendin-4, 0.01, 0.03, 0.1, 1, and 100 pg exendin-4 acid, and 0.1, 0.3, 1, 10 and 100 pg of 1 Leu, 2 Phe exendin-4. Exendin-3, exendin-4 acid and "Leu,"Phe were synthesized according to standard peptide synthesis methods. The results, shown in Figure 3 and Table II, show that the exendin agonists, exendin-4 acid and "Leu, 25 Phe exendin-4, are potent inhibitors of gastric emptying. The ECso of exendin-4 was 0.27 pg. The ECs 0 s of exendin-4 acid and 4 Leu, 2 Phe exendin-4 were comparable 15 (0.12 pg and 0.29 pg, respectively).

TABLE II Cnpound ECs 50 lg) exendin-4 0.27 20 exendin-4 acid 0.12 1 "Leu, 25 Phe exendin-4 0.29

EXAMP

The ability of exendin[9-39], an antagonist of exendin's effects at the cloned GLP-1 receptor, to antagonize the gastric emptying inhibition effect of exendin-4 and GLP-1[7-36]NH 2 was examined according to the methods described in Example 1. Rats were treated with pg exendin-4, 1.0 pg exendin-4 with 0.3 mg exendin[9- 39], 10 pg GLP-1[7-36]NH, 10 pg GLP-1[7-36]NH 2 with 0.3 mg exendin[9-39] or with 0.3 mg exendin 9-39 alone. In these studies, exendin[9-39] was give both subcutaneously (sc) and intravenously The results of these experiments are shown in Figures 4-7.

As shown in Figures 4 and 5, after 20 minutes, the animals treated with exendin-4 showed extremely potent inhibition of gastric emptying, which was not reversed by exendin[9-39]. This occurred regardless of whether the exendin[9-39] was administered sc or iv. Exendin[9-39] alone had no effect on gastric emptying.

As discussed above, exendin[9-39] is a potent antagonist of GLP-1 which binds at the cloned GLP-1 receptor (Fehmann HC, et al., Peptides 15(3): 453-6, 1994; Thorens B, et al., Diabetes 42(11): 1678-82, 1993).

Surprisingly, however, exendin[9-39] did not block the effect of exendin-4 on gastric emptying (see Figures 4 and S 15 These results indicate that the effects of exendins on gastric emptying are not due binding of the exendins at the cloned GLP-1 receptor, but instead that the gastric emptying effects of exendins are due to a different receptor.

20 That exendin[9-39] did not block the effect of GLP- 1[7-36]NH 2 on gastric emptying (see Figures 6 and 7) indicates that, in its effects on gastric emptying, GLP-1 is also acting at a receptor other than the cloned GLP-1 receptor (at which exendin[9-39] is a potent antagonist).

S 25 EXAMPLE Preparation of amidated peptide having SEQ. ID. NO. r51 The above-identified peptide was assembled on 4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.). In general, single-coupling cycles were used throughout the synthesis and Fast Moc (HBTU activation) chemistry was employed. However, at some positions coupling was less efficient than expected and double couplings were required. In particular, residues Asp,, Thr, and Phe -all required double coupling. Deprotection (Fmoc group removal)of the growing peptide chain using piperidine was not always efficient. Double deprotection was required at positions Arg 20 Val,, and Leu, 4 Final deprotection of the completed peptide resin was achieved using a mixture of triethylsilane (0.2 mL), ethanedithiol (0.2 mL), anisole (0.2 mL), water (0.2 mL) and trifluoroacetic acid (15 mL) according to standard methods (Introduction to Cleavage Techniques, Applied Biosystems, Inc.) The peptide was 15 precipitated in ether/water (50 mL) and centrifuged. The precipitate was reconstituted in glacial acetic acid and o S"lyophilized. The lyophilized peptide was dissolved in water). Crude purity was about Used in purification steps and analysis were Solvent 20 A TFA in water) and Solvent B TFA in ACN).

The solution containing peptide was applied to a preparative C-18 column and purified (10% to 40% Solvent B in Solvent A over 40 minutes). Purity of fractions was determined isocratically using a C-18 analytical column.

Pure fractions were pooled furnishing the above-identified peptide. Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of the lyophilized peptide gave product peptide having an observed retention time of 14.5 minutes. Electrospray Mass Spectrometry calculated 4131.7; found 4129.3.

EXAMPLE Preparticn of Peptide having sEo ID NO r6 The above-identified peptide was assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Example 4. Used in analysis were Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 25% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide gave product peptide having an observed retention time of 21.5 minutes. Electrospray SMass Spectrometry calculated 4168.6; found 4171.2.

EXAMPIE 6 Preparation of Peptide having SEQ. ID. NO- [71 The above-identified peptide was assembled on 4- (2'-4'-dimethoxyphenyl)-Pmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 20 mmole/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Example 4. Used in \analysis were Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of the lyophilized peptide gave product peptide having an observed retention time of 17.9 minutes. Electrospray Mass Spectrometry calculated 4147.6; found 4150.2.

EXAMPIE 7 Preparation of Peptide having SEQ. ID. NO. [8] The above-identified peptide was assembled on 4- (2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Example 4. Used in analysis were Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 35% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide gave product peptide having an observed retention time of 19.7 minutes. Electrospray Mass Spectrometry calculated 4212.6; found 4213.2.

EXAMPLE 8 Preparation of Peptide having SEQ. ID. NO. [9] S..The above-identified peptide was assembled on 4-

S

(2'-4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 20 mmole/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Example 4. Used in analysis were Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to 50% Solvent B in Solvent A over 30 minutes) of the lyophilized peptide gave product peptide having an observed retention time of 16.3 minutes. Electrospray Mass Spectrometry calculated 4262.7; found 4262.4.

EXAMPLE 9 pp-aration of Peptide having R EQID. NO._ 101 The above-identified peptide is assembled on 4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamidenorleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Example 4. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN).

Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the oproduct peptide. Electrospray Mass Spectrometry calculated 4172.6 o o, 15 EXAMPLE= Preparation of Peptide having SEQ. ID. NO. [111 The above-identified peptide is assembled on 4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using 20 Fmoc-protected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Example 4. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN).

Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 4224.7.

WO 98/05351 PCT/US97/t4199 38 EXAMPLE 11 Preparation of Peptide having SEO. ID. NO. [121 The above-identified peptide is assembled on 4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Example 4. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN).

Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 4172.6 EXAMPLE 12 prepparation of Ppptide having RO. TID. NO. r111 The above-identified peptide is assembled on 4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide 20 norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a :similar way to Example 4. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN).

25 Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 4186.6 EXAMPLE 13 Preparation of Peptide having SEQ TD. O. [141 The above-identified peptide is assembled on 4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Example 4. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN).

Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 4200.7 15 EXAMPLE 14 Preparation of Peptide having SEQ. ID. NO. [151 The above-identified peptide is assembled on 4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Example 4. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN).

Analytical RP-HPLC (gradient 30% to 60% Solvent B in o*o: 25 Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 4200.7 EXAMPLE Preparation of Peptide having SEQ. TD. NO. r161 The above-identified peptide is assembled on 4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Example 4. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN).

Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 4202.7.

15 EXAMPLE 16 Preparation of Peptide having SEO. ID. NQ. [171 The above-identified peptide is assembled on 4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Example 4. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN).

Analytical RP-HPLC (gradient 30% to 60%.Solvent B in 25 Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 4145.6.

EXAMPTE 17 Preparation of Peptide having SE. ID. NO. 1181 The above-identified peptide is assembled on 4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Example 4. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN).

Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 4184.6.

15 EXAMPLE 18 Preparation of Peptiide having SEQ. ID. NO. [191 The above-identified peptide is assembled on 4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Example 4. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN).

Analytical RP-HPLC (gradient 30% to 60% Solvent B in 25 Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 4145.6.

EXAMPLE 19 preparation of Peptide having EQO. ID. NO. [201 The above-identified peptide is assembled on 4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Example 4. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN).

Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 4224.7.

15 EXAMPLE preparation of Peptide having SE.O TD. NO. [211 The above-identified peptide is assembled on 4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Example 4. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN).

Analytical RP-HPLC (gradient 30% to 60% Solvent B in 25 Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 4172.6.

43 EXAMPLE 2 Preparation of Peptide having SEQ. ID. NO-Q.221 The above-identified peptide is assembled on 4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Example 4. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN).

Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 4115.5.

15 EXAMPE 22 'Preparation of Peptide having SF._ ID. NO. r231 SThe above-identified peptide is assembled on 4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide Snorleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Example 4. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN).

Analytical RP-HPLC (gradient 30% to 60% Solvent B in 25 Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 4188.6.

EXAMPLE 23 Preparation of Peptide having SEO. ID. NO. [241 The above-identified peptide is assembled on 4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Example 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN).

Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 4131.6.

15 EXAMPLE 24 Preparation of Peptide having SEO. TD. NO. r251 The above-identified peptide is assembled on 4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Example 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN).

S. Analytical RP-HPLC (gradient 30% to 60% Solvent B in 25 Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 4172.6.

EXAMPLE preparation of Peptide having SE. ID. NO. [261 The above-identified peptide is assembled on 4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamidenorleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Example 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN).

Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide. Electrospray Mass Spectrometry calculated 4145.6.

S. 15 EXAMPLE 26 Preparation of Peptide having SEO. ID. NO. r271 The above-identified peptide is assembled on 4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using 20 Fmoc-protected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Example 1. Additional double couplings are required at the thioproline positions 38, 37, 36 and c 31. Used in analysis are Solvent A TFA in water) 25 and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent A over minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide.

Electrospray Mass Spectrometry calculated 4266.8.

EXAMPT.E 27 Preparation of Peptide having SEO. ID. NO. r281 The above-identified peptide is assembled on 4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Example 1. Additional double couplings are required at the thioproline positions 38, 37 and 36.

Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent A over minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide.

15 Electrospray Mass Spectrometry calculated 4246.8.

XAMPLE 28 Preparation of Peptide having SEO. ID. NO. r291 The above-identified peptide is assembled on 4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide 20 norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Example 1. Additional double couplings are required at the homoproline positions 38, 37, 36 and 25 31. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent A over minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide.

Electrospray Mass Spectrometry calculated 4250.8.

EXAMPLE 29 Preparation of Peptide having SEQ- ID. NO. 1301 The above-identified peptide is assembled on 4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Example 1. Additional double couplings are required at the homoproline positions 38, 37, and 36. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent A over minutes) of the lyophilized peptide is then carried out 15 to determine the retention time of the product peptide.

Electrospray Mass Spectrometry calculated 4234.8.

F.XAMPLE Preparation of Peptide having SEQ. ID. NO. [311 The above-identified peptide is assembled on 4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide Snorleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Example 1. Additional double couplings are required at the thioproline positions 38, 37, 3 and 31. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent A over 48 minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide.

Electrospray Mass Spectrometry calculated 4209.8.

EXAMPT. 31 Preparation of Peptide having SEO. ID. NO. [321 The above-identified peptide is assembled on 4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Example 1. Additional double couplings are required at the homoproline positions 38, 37, 36 and 31. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC 15 (gradient 30% to 60% Solvent B in Solvent A over minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide.

Electrospray Mass Spectrometry calculated 4193.7.

XAMPLE 32 20 Preparation of Peptide having SEO. ID. NO. 331 *"The above-identified peptide is assembled on S4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Example 1. Additional double couplings are required at the N-methylalanine positions 38, 37, 36 and 31. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP- HPLC (gradient 30% to 60% Solvent B in Solvent A over minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide.

Electrospray Mass Spectrometry calculated 3858.2.- EXAMPLE 33 Preparation of Peptide having REO. ID. NO. [341 The above-identified peptide is assembled on 4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Example 1. Additional double couplings are required at the N-methylalanine positions 38, 37 and 15 36. Used in analysis are Solvent A TFA in water) o. and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent A over minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide.

20 Electrospray Mass Spectrometry calculated 3940.3.

t* EXAMPTE 34 Preparation of Peptide having SEO. TD NO. [351 *see.: SThe above-identified peptide is assembled on 4'-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucine MBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected and purified in a similar way to Example 1. Additional double couplings are required at the N-methylalanine positions 38, 37, 36 and 31. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP- HPLC (gradient 30% to 60% Solvent B in Solvent A over minutes) of the lyophilized peptide is then carried out to determine the retention time of the product peptide.

Electrospray Mass Spectrometry calculated 3801.1.

EXAMPLE Preparation of C-terminal carboxylic acid Peptides corresponding to the above C-terminal amide sequences.

The above peptides are assembled on the so called Wang resin (p-alkoxybenzylalacohol resin (Bachem, 0.54 mmole/g)) using Fmoc-protected amino acids (Applied Biosystems, Inc.), cleaved from the resin, deprotected 15 and purified in a similar way to Example 1. Used in analysis are Solvent A TFA in water) and Solvent B TFA in ACN). Analytical RP-HPLC (gradient 30% to Solvent B in Solvent A over 30 minutes) of the lyophilized peptide is then carried out to determine the 20 retention time of the product peptide. Electrospray Mass Spectrometry provides an experimentally determined

(M)

*o

Claims (49)

1. A method of beneficially regulating gastro-intestinal motility in a subject, the method comprising administering to said subject a therapeutically effective amount of an exendin or an exendin agonist, with the proviso that the exendin agonist is not glucagon-like peptide 1.

2. A method according to claim 1 wherein said beneficial regulation of gastrointestinal motility comprises reducing gastric motility.

3. A method according to claim 1 wherein said beneficial regulation of gastrointestinal motility comprises delaying gastric emptying.

4. The method according to any one of claims 1 to 3, wherein said exendin is exendin-3. The method according to any one of claims 1 to 3, wherein said exendin agonist is exendin-4.

6. The method according to any one of claims 1 to 3, wherein said subject is undergoing a gastrointestinal diagnostic procedure.

7. The method of claim 6 wherein said gastro-intestinal diagnostic procedure is a radiological examination.

8. The method of claim 7 wherein said gastrointestinal diagnostic procedure is magnetic resonance imaging.

9. A method according to any one of claims 1 to 3, wherein said gastric motility is associated with a gastrointestinal disorder. A method according to claim 9 wherein said gastrointestinal disorder is a spasm.

11. A method according to claim 10 wherein said spasm is associated with a disorder selected from the group consisting of acute diverticulitis or a disorder of the biliary tract or a disorder of the Sphincter of Oddi.

12. The method according to any one of claims 1 to 3, wherein said exendin agonist is selected from a peptide compound of the formula: [R:\LIBZ\Vaughan\Prosecutions\452630D I 452630D I.RL2.claimset.doc:VNB 52 1 5 Xaaj Xaa 2 Xaa 3 Gly Thr Xaa 4 Xaas Xaa 6 Xaa 7 Xaa 8 Ser Lys Gin Xaa 9 Glu Glu Glu Ala Val Arg Leu Xaajo Xaa 1 1 Xaa 12 Xaa 13 Leu Lys Asn Gly Gly Xaa 14 Ser Ser Gly Ala Xaa1 5 Xaa 1 6 Xaa 17 Xaa 18 wherein Xaa 1 is His, Arg or Tyr; Xaa 2 is Ser, Gly, Ala or Thr; Xaa 3 is Asp or Glu; Xaa 4 is Phe, Tyr or naphthylalanine; Xaa 5 is Thr or Ser; Xaa 6 is Ser or Thr; Xaa 7 is Asp or Giu; Xaa 8 is Leu, Ile, Val, pentyiglycine or Met; Xaa 9 is Leu, Ile, pentyiglycine, Val or Met; Xaa 10 is Phe, Tyr or naphthyialanine; Xaa 1 1 is le, Val, Leu, pentyiglycine, tert-butyiglycine or Met; Xaa 1 2 is Glu or Asp; :Xaa 1 3 is Trp, Phe, Tyr, or naphthylalanine; Xaa 1 4 Xaa 15 Xaa 16 and Xaa 17 are independently Pro, homoproline, 3Hyp, 4Hyp, :w thioproline, N-alkylglycine, N-alkylpentylglycine or N-alkylalanine; Xaa 8 is Ser, Thr or Tyr; and Z is -OH or -NH 2 with the proviso that the compound does not have the formula of either exendin-3 [SEQ. ID. NO. 1] or exendin-4 [SEQ. ID. NO. 2] and [R:\LlBZ\Vaughan\Prosecutions\452630D I ]452630D1 .RL2.claimfset.doc:VNB 53 pharmaceutically acceptable salts thereof.

13. The method according to any one of claims 1 to 3, wherein said exendin agonist is selected from a peptide compound of the formula: 1 10 Xaal Xaa 2 Xaa 3 Gly Thr Xaa 4 Xaa 5 Xaa 6 Xaa 7 Xaa 8 Ser Lys Gln Xaa 9 Glu Glu Glu Ala Val Arg Leu Xaa 1 Xaa 11 Xaa 12 Xaa 1 3 Leu Lys Asn Gly Gly Xaa 1 i i 1 ~35 ii1 Scr Scr Gly Ala Xaa, 5 Xaa 16 Xaa 1 7 Xaa 1 8 Iz wherein Xaa 1 is His or Arg; Xaa 2 is Ser, Gly; Xaa 3 is Asp or Glu; Xaa 4 is Phe or naphthylalanine; Xaa 5 is Tbr or Ser; Xaa 6 is Ser or Thr; Xaa 7 is Asp or Glu; Xaa 8 is Leu or pentylglycine; Xaa 9 is Leu or pentylglycine; :Xaa 1 O is Phe or naphthylalanine; Xaa 11 is Ile, Val or tert-butylglycine; *Xaa 12 is Glu or Asp; Xaa 1 3 is Trp or Phe; Xaa 14 Xaa 15 Xaa 16 and Xaa 1 7 are independently Pro, homoproline, thioproline or *N-methylalanine; *:Xaa is Ser or Tyr; and Z is -OH or -NH 2 [R:\LIBZ\Vaughan\Prosecutions\452630D I 452630D I .RL2.claimrset.doc:VNB -54- with the proviso that the compound does not have the formula of either exendin-3 [SEQ. ID. NO. 1] or exendin-4 [SEQ. ID. NO. 2] and pharmaceutically acceptable salts thereof.

14. A method of beneficially regulating gastro-intestinal motility in a subject, the method comprising administering to said subject a therapeutically effective amount of an exendin or an exendin agonist, with the proviso that the exendin agonist is not glucagon-like peptide 1, wherein said exendin or said exendin agonist is substantially as hereinbefore described with reference to any one of Examples 4 to An exendin or exendin agonist when used in beneficially regulating gastrointestinal motility in a subject, with the proviso that the exendin agonist is not glucagon-like peptide 1.

16. Use of an exendin or exendin agonist in the manufacture of a medicament in beneficially regulating gastrointestinal motility in a subject, with the proviso that the exendin agonist is not glucagon-like peptide 1.

17. A method of treating a disease or disorder which may be benefited by a decrease in gastrointestinal motility or a delay in gastric emptying [postprandial dumping syndrome] in a subject, the method comprising administering to said subject a therapeutically effective amount of an exendin or exendin agonist that provides for the reduction in gastric motility or delay in gastric emptying, wherein the disease or disorder is postprandial dumping syndrome and with the proviso that the exendin agonist is not glucagon-like peptide 1.

18. The method of claim 17, wherein said exendin or said exendin agonist is substantially as hereinbefore described with reference to any one of Examples 4 to

19. An exendin or exendin agonist when used for treating a disease or disorder which may be benefited by a decrease in gastrointestinal motility or a delay in gastric emptying wherein the disease or disorder is post-prandial dumping syndrome and with the proviso that the exendin agonist is not glucagon-like peptide 1.

20. Use of an exendin or exendin agonist in the manufacture of a medicament for treating a disease or disorder which may be benefited by a decrease in gastrointestinal motility or a delay in gastric emptying wherein the disease or disorder is post-prandial dumping syndrome and with the proviso that the exendin agonist is not glucagon-like peptide 1. [R:\LIBZ\Vaughan\Prosecutions\452630DI ]452630D I.RL2.caimset.doc:VNB

21. A method of treating a disease or disorder which may be benefited by a decrease in gastrointestinal motility or a delay in gastric emptying in a subject, the method comprising administering to the subject a therapeutically effective amount of an exendin or exendin agonist that provides for the reduction in gastric motility or delay in gastric emptying, wherein the disease or disorder is postprandial hyperglycemia that is benefited by a decrease in gastrointestinal motility or a delay in gastric emptying, with the proviso that the exendin agonist is not glucagon-like peptide 1.

22. The method according to claim 21 further comprising administering a therapeutically effective amount of an amylin or an amylin agonist.

23. The method according to claim 22 wherein said amylin agonist is 28Pro, 29Pro-h amylin.

24. The method of any one of claims 21-23, wherein said exendin or said exendin agonist is substantially as hereinbefore described with reference to any one of Examples 4 to 35 with the proviso that the exendin agonist is not glucagon-like peptide 1. An exendin or exendin agonist when used for treating a disease or disorder which may be benefited by a decrease in gastrointestinal motility or a delay in gastric emptying wherein the disease or disorder is postprandial hyperglycemia that is benefited o* by a decrease in gastrointestinal motility or a delay in gastric emptying, with the proviso that the exendin agonist is not glucagon-like peptide 1.

26. Use of an exendin or exendin agonist in the manufacture of a medicament for treating a disease or disorder which may be benefited by a decrease in gastrointestinal motility or a delay in gastric emptying wherein the disease or disorder is postprandial hyperglycemia that is benefited by a decrease in gastrointestinal motility or a delay in gastric emptying, with the proviso that the exendin agonist is not glucagon-like peptide 1.

27. The method of claim 21, wherein the postprandial hyperglycemia is a consequence of type 2 diabetes mellitus.

28. The method of claim 21, wherein the postprandial hyperglycemia is a consequence of type 2 diabetes mellitus and wherein said exendin or said exendin agonist is substantially as hereinbefore described with reference to any one of Examples 4 to with the proviso that the exendin agonist is not glucagon-like peptide 1.

29. A method of treating type 1 diabetes mellitus in a subject, the method comprising administering to the subject a therapeutically effective amount of an exendin [R:\LIBZ\Vaughan\Prosecutions\452630D I 452630D1.RL2.claimsetdoc:VNB 56 or an exendin agonist, wherein said exendin agonist is selected from a peptide compound of the formula: Xaa 1 Xaa 2 Xaa 3 Gly Thr Xaa 4 Xaa 5 Xaa 6 Xaa 7 Xaa8 Ser Lys Gin Xaa 9 Glu Giu Glu Ala Val IArg Leu Xaa 10 Xaaj 1 Xaa 12 Xaa 13 Leu Lys Asn Gly Gly Xaa. 14 Ser Ser Gly Ala Xaa, 5 Xaa 16 Xaa 17 Xaa, 8 wherein Xaa 1 is His, Arg or Tyr; Xaa 2 is Ser, Gly, Ala or Thr; Xaa 3 is Asp or Glu; Xaa 4 is Phe, Tyr or naphthylaianine; Xaa 5 is Thr or Ser; Xaa 6 is Ser or Thr; Xaa 7 is Asp or Glu; 7a 8 i ele a, etilcn rMt Xaa8 is Leu, Ile, Vapentyglycinea or Met; Xaa 1 0 is Phe, Tyr or naphthyialanine; Xaa 11 is Ie, Val, Leu, pentyiglycine, tert-butyiglycine or Met; :Xaa 1 2 is Glu or Asp; Xaa 1 3 is Trp, Phe, Tyr, or naphthylalanine; Xaa 1 4 Xaa 1 5 Xaa 1 6 and Xaa 1 7 are independently Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine or N-alkylalanine; Xaa 8 is Ser, Thr or Tyr; and Z is -OH or -NH 2 and pharmaceutically acceptable salts thereof, [R:\L.IBZ\Vaughan\Prosecutions\452630D I ]452630D1 .RL2.claimsetdoc:VNB 57 with the proviso that the compound does not have the formula of either exendin-3 [SEQ. ID. NO. 1] or exendin-4 [SEQ. ID. NO. and with the proviso that the exendin agonist is not glucagon-like peptide 1, and further that the exendin agonist is not an exendin analogue that: consists of an exendin analog corresponding to positions 1-30, 2-30, or 3-30 of exendin 3 or exendin 4 unless the amino acid at position 30 is glycine; or consists of an exendin analog corresponding to positions 1-27, 1-28, 1-29, 2- 27, 2-28, 2-29, 3-27, 3-28, or 3-29 of exendin 3 or exendin 4. A method of treating type I diabetes mellitus in a subject, the method comprising administering to the subject a therapeutically effective amount of an exendin or an exendin agonist, substantially as hereinbefore described with reference to any one of Examples 4 to 35 wherein said exendin agonist is selected from a peptide compound of the formula: 1_ 5 Xaal Xaa 2 Xaa 3 Gly Thr Xaa 4 Xaa 5 Xaa 6 Xaa 7 Xaa 8 15 Ser Lys Gln Xaag Glu Glu Glu Ala Val Arg Leu 25 Xaalo Xaal 1 Xaa 1 2 Xaa 13 Leu Lys Asn Gly Gly Xaa 1 4 Ser Ser Gly Ala Xaa, 5 Xaa 16 Xaa 17 Xaa 18 S. S S S *SS 55 S S S SS S. S S S S S S S *SS 5555 0 S .55. S S S. S 55 o 0 wherein Xaa 1 is Hi s, Arg or Tyr; Xaa 2 is Ser, Gly, Ala or Thr; Xaa 3 is Asp or Glu; Xaa 4 is Phe, Tyr or naphthylalanine; Xaa 5 is Thr or Ser; Xaa 6 is Ser or Thr; Xaa 7 is Asp or Glu; Xaa 8 is Leu, Ile, Val, pentylglycine or Met; Xaa 9 is Leu, Ie, pentylglycine, Val or Met; Xaa 10 is Phe, Tyr or naphthylalanine; [R:\LIBZ\Vaughan\Prosecutions\452630DI ]452630D1 .RL2.claimset.doc:VNB 58 Xaa 11 is Ile, Val, Leu, pentyiglycine, tert-butyiglycine or Met; Xaa 1 2 is Glu or Asp; Xaa 1 3 is Trp, Phe, Tyr, or naphthylalanine; Xaa 1 4 Xaa 15 Xaa 1 6 and Xaa 1 7 are independently Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine or N-alkylalanine; Xaa 18 is Ser, Thr or Tyr; and Z is -OH or -NH 2 and pharmaceutically acceptable salts thereof, with the proviso that the compound does not have the formula of either exendin-3 [SEQ. ID. NO. 1] or exendin-4 [SEQ. ID. NO. and with the proviso that the exendin agonist is not glucagon-like peptide 1, and further that the exendin agonist is not an exendin analogue that: consists of an exendin analog corresponding to positions 1-30, 2-30, or 3-30 of exendin 3 or exendin 4 unless the amino acid at position 30 is glycine; or consists of an exendin analog corresponding to positions 1-27, 1-28, 1-29, 2- 27, 2-28, 2-5 29, 3-27, 3-28, or 3-29 of exendin 3 or exendin 4.

31. An exendin or exendin agonist when used in treating type 1 diabetes mellitus, wherein said exendin agonist is selected from a peptide compound of the formula: *see .00. .00. z 1 5 Xaa 1 Xaa 2 Xaa 3 Gly Thr Xaa 4 Xaas Xaa 6 Xaa 7 Xaa 8 15 Ser Lys GIn Xaa 9 Glu Glu Glu Ala Val Arg Leu 25 Xaajo Xaall Xaa 12 Xaa 13 Leu Lys Asn Gly Gly Xaa 14 Ser Ser Gly Ala {Xaa 1 5 Xaa 16 Xaa 17 Xaa 18 [R:\LIBZ\Vaughan\Prosecutions\452630D I ]452630D I .RL2.claimset.doc:VNB -59- wherein Xaa, is His, Arg or Tyr; Xaa 2 is Ser, Gly, Ala or Thr; Xaa 3 is Asp or Glu; Xaa 4 is Phe, Tyr or naphthylalanine; Xaa 5 is Thr or Ser; Xaa 6 is Ser or Thr; Xaa, is Asp or Glu; Xaa 8 is Leu, Ile, Val, pentylglycine or Met; Xaa 9 is Leu, Ile, pentylglycine, Val or Met; Xaa 10 is Phe, Tyr or naphthylalanine; Xaa,, is Ile, Val, Leu, pentylglycine, tert-butylglycine or Met; Xaal 2 is Glu or Asp; Xaa 13 is Trp, Phe, Tyr, or naphthylalanine; Xaa 4 Xaa,,, Xaa 1 6 and Xaa 1 7 are independently Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine or N-alkylalanine; Xaa,8 is Ser, Thr or Tyr; and .o ~Z is -OH or -NH 2 and pharmaceutically acceptable salts thereof, with the proviso that the compound does not have the formula of either exendin-3 [SEQ. ID. NO. 1] or exendin-4 [SEQ. ID. NO. and with the proviso that the exendin agonist is not glucagon-like peptide 1, and further that the exendin agonist is not an exendin analog that: consists of an exendin analog corresponding to positions 1-30, 2-30, or 3-30 of exendin 3 or exendin 4 unless the amino acid at position 30 is glycine; or consists of an exendin analog corresponding to positions 1-27, 1-28, 1-29, 2- 27, 2-28, 2-29, 3-27, 3-28, or 3-29 of exendin 3 or exendin 4.

32. Use of an exendin or exendin agonist in the preparation of a medicament for treating type 1 diabetes mellitus, wherein said exendin agonist is selected from a peptide compound of the formula: [R:\LIB7Z\Vaughan\Prosecutions\452630DI ]452630D I.RL2.caimset.doc:VNB 60 1 5 Xaa 1 Xaa 2 Xaa 3 Gly Thr Xaat Xaa 5 Xaa 6 Xaa 7 Xaa 8 Ser Lys Gin Xaa 9 Giu Glu Giu Ala Val Arg Leu Xaa 10 Xaall Xaa 1 2 Xaa 1 3 Leu Lys Asn Gly Giy Xaa 14 Ser Ser Gly Ala Xaa 15 Xaa 1 6 Xaa] 7 Xaa 1 8- z wherein Xaa 1 is His, Arg or Tyr; Xaa 2 is Ser, Gly, Ala or Thr; Xaa 3 is Asp or Glu; Xaa 4 is Phe, Tyr or naphthylaianine; Xaa 5 is Thr or Ser; Xaa 6 is Ser or Thr; Xaa 7 is Asp or Giu; *aa isLu lVapnygyc rMt Xaa 8 is Leu, Ie, Vapentyglycine a or Met; ~Xaa 9 is Le, Tyie, pnatyigl ealor et; 0010 Xaa 11 is Ie, Val, Leu, pentyiglycine, :tert-butyiglycine or Met; Xaa 1 2 is Glu or Asp; ,3is Trp, Phe, Tyr, or naphthylaianine; XaaW 4 Xaa 15 Xaa 16 and Xaa 1 7 are independentiy Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, aa 8 N-alkylpentylglycine or N-alkylalanine; l is Ser, Thr or Tyr; and Z is -OH or -NH 2 and pharmaceutically acceptable salts thereof, with the proviso that the compound does not have the formula of either exendin-3 [SEQ. ID. NO. 1] or exendin-4 [SEQ. ID. NO. and with the proviso that the exendin [R:\L-IBZ\Vaughan\Prnsccutions\452630DI ]452630D1 .RL2.claimsct.doc:VNB -61- agonist is not glucagon-like peptide 1, and further that the exendin agonist is not an exendin analog that: consists of an exendin analog corresponding to positions 1-30, 2-30, or 3-30 of exendin 3 or exendin 4 unless the amino acid at position 30 is glycine; or consists of an exendin analog corresponding to positions 1-27, 1-28, 1-29, 2- 27, 2-28, 2-29, 3-27, 3-28, or 3-29 of exendin 3 or exendin 4.

33. A method of treating a disease or disorder which may be benefited by a decrease in gastrointestinal motility or a delay in gastric emptying in a subject, the method comprising administering to the subject a therapeutically effective amount of an exendin or an exendin agonist that provides for the reduction in gastric motility or delay in gastric emptying, wherein the disease or disorder is impaired glucose tolerance, with the proviso that the exendin agonist is not glucagon-like peptide 1.

34. A method of treating a disease or disorder which may be benefited by a decrease in gastrointestinal .motility or a delay in gastric emptying, the method comprising administering a therapeutically effective amount of an exendin or an exendin agonist that provides for the reduction in gastric motility or delay in gastric emptying, wherein the disease or disorder is impaired glucose tolerance, with the proviso that the exendin agonist is not glucagon-like peptide 1 and which is substantially as hereinbefore described with reference to any one of Examples 4 to

35. An exendin or an exendin agonist when used for treating a disease or disorder which may be benefited by a decrease in gastrointestinal motility or a delay in gastric emptying wherein the disease or disorder is impaired glucose tolerance, with the proviso that the exendin agonist is not glucagon-like peptide 1.

36. Use of an exendin or an exendin agonist in the manufacture of a medicament for treating a disease or disorder which may be benefited by a decrease in gastrointestinal motility or a delay in gastric emptying wherein the disease or disorder is impaired glucose tolerance, with the proviso that the exendin agonist is not glucagon-like peptide 1.

37. A method of treatment for ingestion of a toxin in a subject, the method comprising: is administering to the subject an amount of an exendin or an exendin agonist effective to prevent or reduce the passage of stomach contents to the intestines; and S S 0@ SS S t S 0 OS S S S 9 S 0O S 9 S *9 S S [R:\LIBZ\Vaughan\Prosecutions\452630D I ]452630DI.RL2 .claimset.doc:VNB -62- aspirating the contents of the stomach, with the proviso that the exendin agonist is not glucagon-like peptide 1.

38. A method of treatment for ingestion of a toxin, the method comprising: administering an amount of an exendin or an exendin agonist effective to prevent or reduce the passage of stomach contents to the intestines; and aspirating the contents of the stomach, wherein the exendin or the exendin agonist is substantially as hereinbefore described with reference to any one of Examples 4 to 35 and with the proviso that the exendin agonist is not glucagon-like peptide 1.

39. An exendin or an exendin agonist when used for treatment for ingestion of a toxin with the proviso that the exendin agonist is not glucagon-like peptide 1. Use of an exendin or an exendin agonist in the manufacture of a medicament for treatment for ingestion of a toxin with the proviso that the exendin agonist is not glucagon-like peptide 1.

41. A process for preparing the exendin or an exendin agonist substantially as hereinbefore described with reference to any one of examples 4 to 35, wherein said exendin agonist is selected from a peptide compound of the formula: 1 5 Xaal Xaa 2 Xaa 3 Gly Thr Xaa 4 Xaas Xaa 6 Xaa 7 Xaa 8 15 Ser Lys Gin Xaa 9 Glu Glu Glu Ala Val Arg Leu 25 Xaalo Xaall Xaal2 Xaa 1 3 Leu Lys Asn Gly Gly Xaal4 Ser Ser Gly Ala Xaals Xaa 16 Xaal7 Xaa 1 s- Z 0 S S 0@ 0@ 0 r S 6 0**SO ISS 6 5 0 S wherein Xaa, is His, Arg or Tyr; Xaa 2 is Ser, Gly, Ala or Thr; Xaa 3 is Asp or Glu; Xaa 4 is Phe, Tyr or naphthylalanine; Xaa 5 is Thr or Ser; Xaa 6 is Ser or Thr; Xaa 7 is Asp or Glu; [R:\LIBZ\Vaughan\Prosecutions\452630DI ]452630DI .RL2.claimset.doc:VNB -63- Xaa 8 is Leu, Ile, Val, pentylglycine or Met; Xaa 9 is Leu, Ile, pentylglycine, Val or Met; Xaao 0 is Phe, Tyr or naphthylalanine; Xaa,, is Ile, Val, Leu, pentylglycine, tert-butylglycine or Met; Xaal 2 is Glu or Asp; Xaa,3 is Trp, Phe, Tyr, or naphthylalanine; Xaal4, Xaa,5, Xaa 16 and Xaa 7 are independently Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine or N-alkylalanine; Xaa 1 8 is Ser, Thr or Tyr; and Z is -OH or -NH 2 and pharmaceutically acceptable salts thereof, with the proviso that the compound does not have the formula of either exendin-3 S: [SEQ. ID. NO. 1] or exendin-4 [SEQ. ID. NO. and with the proviso that the exendin agonist is not glucagon-like peptide 1, and further that the exendin agonist is not an Sexendin analog that: consists of an exendin analog corresponding to positions 1-30, 2-30, or 3-30 of exendin 3 or exendin 4 unless the amino acid at position 30 is glycine; or consists of an exendin analog corresponding to positions 1-27, 1-28, 1-29, 2- 27, 2-28, 2-29, 3-27, 3-28, or 3-29 of exendin 3 or exendin 4.

42. An exendin or an exendin agonist prepared in accordance with the process of claim 41.

43. A method of treating a disease or disorder which may be benefited by a :o decrease in gastrointestinal motility or a delay in gastric emptying in a subject, the method comprising administering to the subject a therapeutically effective amount of an exendin or exendin agonist that provides for the reduction in gastric motility or delay in gastric emptying, wherein the disease or disorder is postprandial hyperglycemia that is benefited by a decrease in gastrointestinal motility or a delay in gastric emptying, wherein said exendin agonist is selected from a peptide compound of the formula: [R:\LIBZ\Vaughan\Prosecutions\452630DI ]452630DI.RL2.claimset.doc:VNB 64 1 5 Xaa 1 Xaa 2 Xaa 3 Gly Thr Xaa 4 Xaa 5 Xaa 6 Xaa 7 Xaa 8 Scr Lys Gin Xaa 9 Glu Glu Glu Ala Val Arg Leu Xaajo Xaaj 1 Xaa 12 Xaa1 3 Leu Lys Asn Gly Gly Xaa 14 Ser Ser Gly Ala Xaa 15 Xaa 16 Xaa 17 Xaa 18 wherein Xaa 1 is His, Arg or Tyr; Xaa 2 is Ser, Gly, Ala or Thr; Xaa 3 is Asp or Glu; Xaa 4 is Phe, Tyr or naphthylalanine; Xaa 5 is Thr or Ser; Xaa 6 is Ser or Thr; Xaa 7 is Asp or Glu; Xaa 8 is Leu, Ile, Val, pentyiglycine or Met; Xaa 9 is Leu, le, pentyiglycine, Val or Met; Xaa 10 is Phe, Tyr or naphthylalanine; Xaa 1 1 is Ile, Val, Leu, pentyiglycine, tert-butylglycine or Met; Xaa 1 2 is Glu or Asp; Xaa 13 is Trp, Phe, Tyr, or naphthylalanine; Xaa 14 Xaa 1 5 Xaa 1 6 and Xaa 17 are independently Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine or N-alkylalanine; Xaa 1 8 is Ser, Thr or Tyr; and Z is -OH or -NH 2 and pharmaceutically acceptable salts thereof, with the proviso that the compound does not have the formula of either exendin-3 [SEQ. ID. NO. 1] or exendin-4 [SEQ. ID. NO. and with the proviso that the exendin agonist is not glucagon-like peptide 1. [R:\LIBZ\Vaughan\Prosecutions\452630D I ]452630D I.RL2.claimsct.dac:VNB

44. The method according to claim 43 further comprising administering a therapeutically effective amount of an amylin or an amylin agonist. The method according to claim 44 wherein said amylin agonist is 28Pro, 29Pro-h amylin.

46. The method of any one of claims 43-45, wherein said exendin or said exendin agonist is substantially as hereinbefore described with reference to any one of Examples 4 to 35 with the proviso that the exendin agonist is not glucagon-like peptide 1.

47. An exendin or exendin agonist when used for treating a disease or disorder which may be benefited by a decrease in gastrointestinal motility or a delay in gastric emptying wherein the disease or disorder is postprandial hyperglycemia that is benefited by a decrease in gastrointestinal motility or a delay in gastric emptying, wherein said exendin agonist is selected from a peptide compound of the formula: 1 5 Xaal Xaa 2 Xaa 3 Gly Thr Xaa 4 Xaa 5 Xaa 6 Xaa 7 Xaa 8 15 Ser Lys Gln Xaa 9 Glu Glu Glu Ala Val Arg Leu 25 Xaalo Xaall Xaal2 Xaa 1 3 Leu Lys Asn Gly Gly Xaal4 Ser Ser Gly Ala Xaais Xaal6 Xaal7 Xaa 1 s- Z__ wherein Xaa, Xaa 2 Xaa 3 Xaa 4 Xaa 5 Xaa 6 Xaa 7 is His, Arg or Tyr; is Ser, Gly, Ala or Thr; is Asp or Glu; is Phe, Tyr or naphthylalanine; is Thr or Ser; is Ser or Thr; is Asp or Glu; Xaa 8 is Leu, Ile, Val, pentylglycine or Met; Xaa 9 is Leu, Ile, pentylglycine, Val or Met; Xaao is Phe, Tyr or naphthylalanine; Xaa,, is Ile, Val, Leu, pentylglycine, [R:\LIBZVaughan\Prosecutions\452630DI 452630DI.RL2.claimset.doc:VNB 66 tert-butyiglycine or Met; Xaa 1 2 is Glu or Asp; Xaa 13 is Trp, Phe, Tyr, or naphthylalanine; XaaW 4 Xaa 1 5 Xaa 1 6 and Xaa 1 7 are independently Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine or N-alkylalanine; Xaa 18 is Ser, Thr or Tyr; and Z is -OH or -NH 2 and pharmaceutically acceptable salts thereof, with the proviso that the compound does not have the formula of either exendin-3 [SEQ. ID. NO. 1] or exendin-4 [SEQ. ID. NO. and with the proviso that the exendin agonist is not glucagon-like peptide 1.

48. Use of an exendin or exendin agonist in the manufacture of a medicament for treating a disease or disorder which may be benefited by a decrease in gastrointestinal motility or a delay in gastric emptying wherein the disease or disorder is postprandial hyperglycemnia that is benefited by a decrease in gastrointestinal motility or a delay in gastric emptying, wherein said exendin agonist is selected from a peptide compound of the formula: a a a. a a. 1_ 5 Xaa 1 Xaa 2 Xaa 3 Gly Thr Xaa 4 Xaa 5 Xaa 6 Xaa 7 Xaa8 15 Ser Lys Gln Xaa 9 Glu Glu Glu Ala Val Arg Leu Xaaj 0 Xaa 11 Xaa 12 Xaa 13 Leu Lys Asn Gly Gly Xaa] 4 Ser Ser Gly Ala Xaa 15 Xaa 16 Xaa 17 Xaa 18 z wherein Xaa 1 is His, Arg or Tyr; Xaa 2 is Ser, Gly, Ala or Thr; Xaa 3 is Asp or Glu; Xaa 4 is Phe, Tyr or naphthylalanine; [R:\LIBZ\Vaughan\Prosecutions\452630D I]452630D I.RL2.claimsct.doc:VNB -67- Xaa 5 is Thr or Ser; Xaa 6 is Ser or Thr; Xaa 7 is Asp or Glu; Xaa 8 is Leu, Ile, Val, pentylglycine or Met; Xaa 9 is Leu, Ile, pentylglycine, Val or Met; Xaao is Phe, Tyr or naphthylalanine; Xaal is Ile, Val, Leu, pentylglycine, tert-butylglycine or Met; Xaal2 is Glu or Asp; Xaa 3 is Trp, Phe, Tyr, or naphthylalanine; Xaal 4 Xaa 5 Xaa, 6 and Xaa 7 are independently Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine or N-alkylalanine; Xaa,8 is Ser, Thr or Tyr; and Z is -OH or -NH 2 and pharmaceutically acceptable salts thereof, with the proviso that the compound does not have the formula of either exendin-3 [SEQ. ID. NO. 1] or exendin-4 [SEQ. ID. NO. and with the proviso that the exendin agonist is not glucagon-like peptide 1.

49. The method of claim 43, wherein the postprandial hyperglycemia is a consequence of type 2 diabetes mellitus.

50. The method of claim 43, wherein the postprandial hyperglycemia is a consequence of type 2 diabetes mellitus and wherein said exendin or said exendin agonist S is substantially as hereinbefore described with reference to any one of Examples 4 to S* with the proviso that the exendin agonist is not glucagon-like peptide 1.

51. An exendin or exendin agonist when used for treating a disease or disorder which may be benefited by a decrease in gastrointestinal motility or a delay in gastric emptying wherein the disease or disorder is postprandial hyperglycemia that is benefited by a decrease in gastrointestinal motility or a delay in gastric emptying, wherein said exendin agonist is selected from a peptide compound of the formula: [R:\LIBZ\Vaughan\Prosecutions\452630D1 I452630D I .RL2.caimset.doc:VNB 68 1 5 10 Xaaj Xaa 2 Xaa 3 Gly Thr Xaa 4 Xaa 5 Xaa 6 Xaa 7 Xaa8 Ser Lys Gin Xaa 9 Glu Glu Glu Ala Val Arg Leu Xaajo Xaa 1 1 Xaa 12 Xaa 13 Leu Lys Asn Gly Gly Xaa 14 Ser Ser Gly Ala Xa 1 5 Xaa 16 Xaa 17 Xaal 8 wherein Xaa 1 is His, Arg or Tyr; Xaa 2 is Ser, Gly, Ala or Thr; Xaa 3 is Asp or Glu; Xaa 4 is Phe, Tyr or naphthylalanine; Xaa 5 is Thr or Ser; Xaa 6 is Ser or Thr; Xaa 7 is Asp or Glu; Xaa 8 is Leu, Ile, Val, pentyiglycine or Met; Xaa 9 is Leu, le, pentyiglycine, Val or Met; Xaa 10 is Phe, Tyr or naphthylalanine; Xaa 1 is Ie, Val, Leu, pentyiglycine, tert-butyiglycine or Met; Xaa 1 2 is Glu or Asp; Xaa 1 3 is Trp, Phe, Tyr, or nptyaaie Xaa 1 4 Xaa 1 5 Xaa 1 6 and Xaa 17 are independently Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-aikyiglycine, N-alkylpentylgiycine or N-alkylaianine; Xaa 18 is Ser, Thr or Tyr; and Z is -OH or -NH 2 and pharmaceutically acceptable salts thereof, with the proviso that the compound does not have the formula of either exendin-3 [SEQ. ID. NO. 1] or exendin-4 [SEQ. ID. NO. and with the proviso that the exendin agonist is not glucagon-like peptide 1. [R:\LIBZ\Vaughan\Prosecutions\452630DI ]452630D1 .RL2.claimfset.doc:VNB 69

52. Use of an exendin or exendin agonist in the manufacture of a medicament for treating a disease or disorder which may be benefited by a decrease in gastrointestinal motility or a delay in gastric emptying wherein the disease or disorder is postprandial hyperglycemnia that is benefited by a decrease in gastrointestinal motility or a delay in gastric emptying, wherein said exendin agonist is selected from a peptide compound of the formula: 1 5 Xaaj Xaa 2 Xaa 3 Gly Thr Xaa 1 Xaa 5 Xaa 6 Xaa 7 Xaag Ser Lys Gln Xaa 9 Glu Glu Glu Ala Val Arg Leu Xaa 10 Xaal 1 Xaa 12 Xaa 13 Leu Lys Asn Gly Gly Xaa 14 Ser Ser Gly Ala Xaa 1 5 Xaa 16 Xaa 17 Xaa 18 wherein Xaa 1 is His, Arg or Tyr; Xaa 2 is Ser, Gly, Ala or Thr; Xaa 3 is Asp or Glu; Xaa 4 is Phe, Tyr or naphthylalanine; Xaa 5 is Thr or Ser; Xaa 6 is Ser or Thr; Xaa 7 is Asp or Glu; Xaa 8 is Leu, Ile, Val, pentylglycine or Met; Xaa 9 is Leu, Ile, pentyiglycine, Val or Met; Xaa 10 is Phe, Tyr or naphthylalanine; Xaa 11 is le, Val, Leu, pentylglycine, tert-butylglycine or Met; Xaa 1 2 is Glu or Asp; Xaa 1 3 is Trp, Phe, Tyr, or naphthylalanine; Xaa 14 Xaa 1 5 Xaa 1 6 and Xaa 1 7 are independently Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, [R:\LII3Z\Vaughan\Prosecutions\452630DI j452630D I.RL2.claimset.doc:VNB 70 N-alkylpentylglycine or N-alkylalanine; Xaa 8 is Ser, Thr or Tyr; and Z is -OH or -NH 2 and pharmaceutically acceptable salts thereof, with the proviso that the compound does not have the formula of either exendin-3 [SEQ. ID. NO. 1] or exendin-4 [SEQ. ID. NO. and with the proviso that the exendin agonist is not glucagon-like peptide 1.

53. A method of treating a disease or disorder which may be benefited by a decrease in gastrointestinal motility or a delay in gastric emptying in a subject, the method comprising administering to the subject a therapeutically effective amount of an exendin or an exendin agonist that provides for the reduction in gastric motility or delay in gastric emptying, wherein the disease or disorder is impaired glucose tolerance, wherein said exendin agonist is selected from a peptide compound of the formula: 5 Xaal Xaa 2 Xaa 3 Gly Thr Xaa 4 Xaa 5 Xaa 6 Xaa 7 Xaa 8 15 Ser Lys Gln Xaa 9 Glu Glu Glu Ala Val IArg Leu 25 Xaalo Xaall Xaa 12 Xaa 13 Leu Lys Asn Gly Gly Xaa 14 Ser Ser Gly Ala Xaa 15 Xaa 16 Xaa 17 Xaa 18 z S 0 wherein Xaa 1 is His, Arg or Tyr; Xaa 2 is Ser, Gly, Ala or Thr; Xaa 3 is Asp or Glu; Xaa 4 is Phe, Tyr or naphthylalanine; Xaa 5 is Thr or Ser; Xaa 6 is Ser or Thr; Xaa 7 is Asp or G1iu; Xaa 8 is Leu, Ile, Val, pentylglycine or Met; Xaa 9 is Leu, Ile, pentylglycine, Val or Met; Xaa 10 is Phe, Tyr or naphthylalanine; [R:\LIBZ\Vaughan\Prosecutions\452630DI ]452630D1 .RL2.claimset.doc:VNB Xaa,, is Ile, Val, Leu, pentylglycine, tert-butylglycine or Met; Xaal2 is Glu or Asp; Xaa, 3 is Trp, Phe, Tyr, or naphthylalanine; Xaal4, Xaa,5, Xaa 16 and Xaa 7 are independently Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine or N-alkylalanine; Xaag 8 is Ser, Thr or Tyr; and Z is -OH or -NH 2 and pharmaceutically acceptable salts thereof, with the proviso that the compound does not have the formula of either exendin-3 [SEQ. ID. NO. 1] or exendin-4 [SEQ. ID. NO. and with the proviso that the exendin agonist is not glucagon-like peptide 1.

54. A method of treating a disease or disorder which may be benefited by a decrease in gastrointestinal motility or a delay in gastric emptying, the method comprising administering a therapeutically effective amount of an exendin or an exendin agonist that provides for the reduction in gastric motility or delay in gastric emptying, wherein the disease or disorder is impaired glucose tolerance, wherein said exendin agonist is selected from a peptide compound of the formula: 9 9 9999 9* 0 1 5 Xaal Xaa 2 Xaa 3 Gly Thr Xaa4 Xaa 5 Xaa 6 Xaa 7 Xaa 8 15 Ser Lys Gin Xaa 9 Glu Glu Glu Ala Val Arg Leu 25 Xaalo Xaall Xaal2 Xaa 13 Leu Lys Asn Gly Gly Xaal4 Ser Ser Gly Ala Xaa 15 Xaai6 Xaa] 7 Xaa 1 s- Z wherein Xaa, is His, Arg or Tyr; Xaa 2 is Ser, Gly, Ala or Thr; [R:\LI3Z\Vaughan\Prosecutions\452630D I ]452630D1 .RL2.cairset.doc:VNB -72- Xaa 3 is Asp or Glu; Xaa 4 is Phe, Tyr or naphthylalanine; Xaa, is Thr or Ser; Xaa 6 is Ser or Thr; Xaa 7 is Asp or Glu; Xaa 8 is Leu, Ile, Val, pentylglycine or Met; Xaa 9 is Leu, Ile, pentylglycine, Val or Met; Xaa 1 l is Phe, Tyr or naphthylalanine; Xaa,, is Ile, Val, Leu, pentylglycine, tert-butylglycine or Met; Xaal2 is Glu or Asp; Xaa 3 is Trp, Phe, Tyr, or naphthylalanine; Xaal4, Xaa 15 Xaal6 and Xaa 17 are independently Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, X aa, N-alkylpentylglycine or N-alkylalanine; Si.: Xaag is Ser, Thr or Tyr; and o Z is -OH or -NH 2 and pharmaceutically acceptable salts thereof, with the proviso that the compound does not have the formula of either exendin-3 [SEQ. ID. NO. 1] or exendin-4 [SEQ. ID. NO. and with the proviso that the exendin Sagonist is not glucagon-like peptide 1 and which is substantially as hereinbefore described with reference to any one of Examples 4 to

55. An exendin or an exendin agonist when used for treating a disease or disorder which may be benefited by a decrease in gastrointestinal motility or a delay in gastric emptying wherein the disease or disorder is impaired glucose tolerance, wherein said exendin agonist is selected from a peptide compound of the formula: 1 I 5 110 Xaal Xaa 2 Xaa 3 Gly Thr Xaa 4 Xaas Xaa 6 Xaa 7 Xaa 8 Ser Lys Gin Xaa 9 Glu Glu Glu Ala Val Arg Leu [R:\LIBZ\Vaughan\Prosecutions\452630DI ]452630D .RL2.claimset.doc:VNB 73 Xaajo Xaall Xaa 12 Xaa 13 Leu Lys Asn -Gly Gly Xaa 14 Ser Ser Gly Ala Xaa, 5 Xaa 16 Xaa 17 Xaa 18 wherein Xaa 1 is His, Arg or Tyr; Xaa 2 is Ser, Gly, Ala or Thr; Xaa 3 is Asp or Glu; Xaa 4 is Phe, Tyr or naphthylalanine; Xaa 5 is Thr or Ser; Xaa 6 is Ser or Thr; Xaa 7 is Asp or Giu; Xaa 8 is Leu, le, Val, pentyiglycine or Met; Xaa 9 is Leu, Ile, pentyiglycine, Val or Met; Xaa 1 0 is Phe, Tyr or naphthylalanine; Xaa 11 is Ile, Val, Leu, pentylglycine, 0 tert-butyiglycine or Met; Xaa 1 is Glu or Asp; 12 06 Xaa 13 is Trp, Phe, Tyr, or naphthylalanine; 0. 6 0.:Xaa 1 4 Xaal 5 Xaa 1 6 and Xaa 1 7 are independently Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, .0*0 N-alkylpentylglycine or N-alkylalanine; Xaa 1 8 is Ser, Thr or Tyr; and oo Z is -OH or -NH 2 and pharmaceutically acceptable salts thereof, 0 o".with the proviso that the compound does not have the formula of either exendin-3 0 [SEQ. ID. NO. 1] or exendin-4 [SEQ. ID. NO. and with the proviso that the exendin agonist is not glucagon-like peptide 1.

56. Use of an exendin or an exendin agonist in the manufacture of a medicament for treating a disease or disorder which may be benefited by a decrease in gastrointestinal motility or a delay in gastric emptying wherein the disease or disorder is [R:\LIBZ\Vaughan\Prosecutions\452630D I ]452630D1I.RL2.claimset.doc:VNB 74 impaired glucose tolerance, wherein said exendin agonist is selected from a peptide compound of the formula: 1_ 5 10 Xaa 1 Xaa. 2 Xaa 3 Gly Thr Xaa 4 Xaa 5 Xaa. 6 Xaa 7 Xaa 8 Ser Lys Gln Xaa 9 Glu Glu Glu Ala Val Arg Leu Xaa 10 Xaall Xaa 1 2 Xaa 13 Leu Lys Asn Gly Gly Xaa 14 Ser Ser Gly Ala Xaa 15 Xaa 16 Xaa 17 Xaa 18 z_ wherein Xaa 1 is H is, Arg or Tyr; Xaa 2 is Ser, Gly, Ala or Thr; Xaa 3 is Asp or Glu; Xaa 4 is Phe, Tyr or naphthylalanine; Xaa 5 is Thr or Ser; Xaa 6 is Ser or Thr; :0 Xaa 7 is Asp or Glu; Xaa 8 is Leu, le, Val, pentylglycine or Met; SO Xaa 9 is Leu, le, pentylglycine, Val or Met; 10 is Phe, Tyr or naphthylalanine; Xaa 1 1 ,is Ie, Val, Leu, pentylglycine, tert-butylglycine or Met; Xaa 1 2 is Glu or Asp; Xaa 1 3 is Trp, Phe, Tyr, or naphthylalanine; XaaW 4 Xaa 15 Xaa 1 6 and Xaa 1 7 are independently 0 Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N-aikyipentylglycine or N-alkylailanine,- Xaa 1 8 is Ser, Thr or Tyr; and Z is -OH or -NH 2 and pharmaceutically acceptable salts thereof, [R:\LIBZ\Vaughan\Prosecutions\452630D I ]452630D1 .RL2.claimset.doc:VNB 75 with the proviso that the compound does not have the formula of either exendin-3 [SEQ. ID. NO. 1] or exendin-4 [SEQ. ID. NO. and with the proviso that the exendin agonist is not glucagon-like peptide 1. 0 all 0 S 0 0S 0 0 0* 0 0 0 960 0 [R:\LIBZ\Vaughan\Prosecutions\452630D I ]452630D I.RL2.cIaimset.doc:VNB