JP7007559B2 - Use of prophylactic and therapeutic agents for cataracts, as well as inhibitors to produce them that block signaling pathways in response to DNA damage - Google Patents

Description

The present invention relates to prophylactic and therapeutic agents for cataracts, as well as the use of inhibitors to produce them that block signaling pathways in response to DNA damage.

Cataract is a disease in which the crystalline lens becomes cloudy (for example, cloudy), resulting in decreased visual acuity. In people with cataracts, opacity generally occurs in the lens, nucleus, cortex, or posterior capsule.

Examples of the type of cataract include age-related cataract and diabetic cataract. Age-related cataracts are the most affected cataracts. In the case of age-related cataract, the number of affected people increases with aging, and about 66-85% of Japanese in their 60s, about 84-97% of Japanese in their 70s, and Japan over 80 years old. There are reports that approximately 100% of people suffer from age-related cataracts. On the other hand, in the case of diabetic cataract, many people are 60 years old or younger, and diabetic cataract is a disease that can occur even in young people.

Examples of the method for treating cataract include surgery and administration of a prophylactic or therapeutic agent. Examples of the prophylactic and therapeutic agents include glutathione and agents containing pyrenoxin (see Non-Patent Documents 1 and 2).

Matensson.J et.al. (1989) Glutathione ester prevents buthionine sulfoximine-induced cataracts and lens epithelial cell damage, Proc Natl Acad Sci USA, vol.86, pp.8727-8731. Ciuffi.M et.al. (1999) Protective Effect of Pirenoxine and U74389F on Induced Lipid Peroxidation in Mammalian Lenses. An in vitro, ex vivo and in vivo study, EXPERIMENTAL EYE RESEARCH, vol.68, pp.347-359.

However, the above-mentioned conventional techniques have room for improvement in the preventive effect and the therapeutic effect of cataract, and it is desired to develop a preventive agent and a therapeutic agent for cataract having a different mechanism of action from the conventional ones.

The present invention has been made in view of the above-mentioned conventional problems, and is a preventive agent and a therapeutic agent for cataract having a different mechanism of action from the conventional ones, and signal transduction in response to DNA damage for producing these. It is intended to provide the use of inhibitors that block the pathway.

We show that signaling pathways that respond to DNA damage (in other words, intracellular and / or extracellular signaling pathways activated by DNA damage) are involved in the onset and severity of cataracts. Based on its own hypothesis, it has been studied repeatedly, and it has been found that cataracts can be prevented and treated by an inhibitor that inhibits a signal transduction pathway that responds to DNA damage, and the present invention has been completed. That is, one embodiment of the present invention has the following configuration.

<1> A preventive or therapeutic agent for cataract, which contains as an active ingredient an inhibitor that inhibits a signal transduction pathway that responds to DNA damage.

<2> The above inhibitors are PLK3 inhibitor, ATM inhibitor, ATR inhibitor, p53 inhibitor, CHK1 inhibitor, CHK2 inhibitor, WEE1 inhibitor, Plk1 inhibitor, Aurora A kinase inhibitor, DNA replication inhibitor. The cataract preventive agent according to <1>, which is one or more selected from the group consisting of a DNA synthesis inhibitor, a thread division inhibitor, a CDC25a inhibitor, a CDC25c inhibitor, and a DNA-PK inhibitor. Or a therapeutic agent.

<3> The above-mentioned inhibitor includes a compound containing a monoprime ring in its structure, a compound containing a heterocyclic ring in its structure, a compound containing both a monoprime ring and a heterocyclic ring in its structure, and a compound. The preventive or therapeutic agent for cataract according to <2>, which is one or more selected from the group consisting of compounds containing an amide bond in the structure.

<4> The preventive or therapeutic agent for cataract according to any one of <1> to <3>, which is an eye drop.

<5> The cataract preventive agent or therapeutic agent according to any one of <1> to <4>, wherein the cataract is a diabetic cataract.

<6> Use of an inhibitor that inhibits a signal transduction pathway that responds to DNA damage for producing a preventive or therapeutic agent for cataract.

According to one aspect of the present invention, it is possible to provide a preventive agent and a therapeutic agent for cataract, which have a different mechanism of action from the conventional ones.

It is a model figure which shows the example of the mechanism of action of the preventive agent or the therapeutic agent of cataract which concerns on one Embodiment of this invention. It is a figure which shows the effect to the cataract of the preventive agent or the therapeutic agent of cataract which concerns on Example of this invention. It is a figure which shows the effect to the cataract of the preventive agent or the therapeutic agent of cataract which concerns on Example of this invention. It is a figure which shows the effect to the cataract of the preventive agent or the therapeutic agent of cataract which concerns on Example of this invention. It is a figure which shows the effect to the cataract of the preventive agent or the therapeutic agent of cataract which concerns on Example of this invention. It is a figure which shows the effect to the cataract of the preventive agent or the therapeutic agent of cataract which concerns on Example of this invention.

An embodiment of the present invention will be described below, but the present invention is not limited thereto. The present invention is not limited to the configurations described below, and various modifications can be made within the scope of the claims, and the technical means disclosed in different embodiments and examples can be used. Embodiments and examples obtained by appropriately combining them are also included in the technical scope of the present invention. In addition, all of the documents described herein are incorporated herein by reference. In the present specification, when the numerical range is described as "A to B", the description is intended to be "A or more and B or less".

[1. Basic Principle of the Invention]
The basic principle of the present invention will be described with reference to FIG.

The present inventor has conventionally conducted a test on cataract using an ex vivo diabetic cataract model using a galactose-added medium. However, the mechanism by which galactose causes cataracts and the mechanism by which galactose aggravates cataracts have been unclear.

In the course of the study, the inventor makes his own hypothesis that galactose may develop and / or aggravate cataracts by the mechanism briefly described in FIG. It came to.

In this mechanism, first, active oxygen (ROS: Reactive Oxygen Species), galactitol, and advanced glycation end products (AGEs) are generated by galactose, and active oxygen, galactitol, and advanced glycation end products (AGEs) are generated. Causes damage to DNA (eg, chromosomal DNA).

When DNA damage is triggered, various signaling pathways are activated intracellularly and / or extracellularly. Various substances (for example, proteins) are involved in the signal transduction pathway, and FIG. 1 shows, as an example, ATM (ataxia telangiectasia mutated (protein kinase)) and PLK3 (Polo-like kinase 3). , And p53 are described. However, to date, many substances have been reported that are involved in signaling pathways that respond to DNA damage. Therefore, the active ingredient contained in the preventive or therapeutic agents for cataract described below includes inhibitors of any substance involved in the signal transduction pathway in response to DNA damage.

Downstream of the signaling pathways that respond to DNA damage described above, there are additional signaling pathways for developing and aggravating cataracts. Therefore, galactose activates signaling pathways that respond to DNA damage and additional signaling pathways to develop and aggravate cataracts, resulting in the onset and severity of cataracts. ..

To confirm that the proprietary hypothesis described above is correct, we tested whether inhibitors that block signaling pathways in response to DNA damage are effective in the prevention or treatment of cataracts. ..

Then, as shown in Examples described later, it became clear that the inventor's hypothesis was correct, and as a result, the inventor came to complete the present invention.

[2. Definition of terms〕
[2-1. Cataract]
As used herein, the term "cataract" is intended to be a disease that causes opacity (eg, opacity) in the crystalline lens. Cataract-induced opacity in the lens includes, for example, cortical opacity; nuclear opacity; posterior subcapsular opacity; cortical spoke-like opacity; anterior subcapsular opacity; fibrous folds, water gaps, or perinuclear point-like opacity; There are types such as blisters; punctate opacity; crown opacity. In addition, "cataract" in the present specification includes age-related cataract and comorbid cataract (for example, diabetic cataract, congenital cataract, traumatic cataract, atopy cataract, radiation cataract, and steroid cataract).

As used herein, "diabetic cataract" is a disease characterized by a persistently elevated glucose concentration in blood or plasma (eg, hyperglycemia, or diabetes (eg, type 1 diabetes, etc.). Alternatively, it is intended to cause opacity of the crystalline body, which affects patients with type 2 diabetes)). Large-scale epidemiological studies have shown that diabetic cataracts often result in opacity in the cortex or subcapsular region of the lens, but the location of opacity is not limited to these.

[2-2. Preventive agent]
As used herein, the term "preventive agent" is intended to be an agent that has a preventive effect. The preventive effect is intended, but is not limited to, the effects exemplified below.
(1) When a preventive agent is administered, the onset of one or more symptoms related to the disease is prevented or the risk of developing the disease is reduced as compared with the case where the preventive agent is not administered.
(2) Compared with the case where the preventive agent is not administered, when the preventive agent is administered, the recurrence of one or more symptoms related to the disease is prevented or the risk of recurrence is reduced.
(3) Preventing or reducing the risk of symptoms of one or more symptoms associated with the disease when the prophylactic agent is administered, as compared to the case where the prophylactic agent is not administered. do.

The one or more symptoms associated with the disease may be systemic or local.

[2-3. Therapeutic agent]
As used herein, the term "therapeutic agent" is intended to be an agent that provides a therapeutic effect. The therapeutic effect is intended, but is not limited to, the effects exemplified below.
(1) When the therapeutic agent is administered, the severity of one or more symptoms related to the disease is reduced as compared with the case where the therapeutic agent is not administered.
(2) When the therapeutic agent is administered, the severity of one or more symptoms related to the disease is prevented from increasing or progressing, as compared with the case where the therapeutic agent is not administered.
(3) When the therapeutic agent is administered, the rate of increase in the severity of one or more symptoms related to the disease or the rate of progression of the severity is reduced as compared with the case where the therapeutic agent is not administered. ..

The one or more symptoms associated with the disease may be systemic or local.

[3. Inhibitors that block signaling pathways in response to DNA damage]
DNA (eg, chromosomal DNA) is damaged by exogenous factors (eg, radiation, UV light, and drugs, etc.) and / or endogenous factors (eg, free radicals, and intracellular metabolites, etc.). I can receive it. When DNA is damaged, various signaling pathways are activated intracellularly and / or extracellularly, thereby repairing the DNA. "Signal transduction pathways that respond to DNA damage" include all signal transduction pathways that are activated during the process of DNA repair, and are "inhibitors that inhibit signal transduction pathways that respond to DNA damage." Includes any inhibitor that inhibits signal transduction in any signal transduction pathway that is activated during the process of DNA repair.

The inhibitor may inhibit the function of a protein constituting a signal transduction pathway activated in the process of DNA repair.

More specifically, the above-mentioned inhibitors include PLK3 (Polo-like kinase 3) inhibitors, ATM (ataxia telangiectasia mutated (protein kinase)) inhibitors, ATR (ATM and Rad3-related (protein kinase)) inhibitors, and the like. p53 inhibitor, CHK1 (Checkpoint kinase 1) inhibitor, CHK2 (Checkpoint kinase 2) inhibitor, WEE1 (Wee1 kinase) inhibitor, PLK1 (Polo-like kinase 1) inhibitor, Aurora A kinase inhibitor, DNA replication inhibition From agents, DNA synthesis inhibitors, thread division inhibitors, CDC 25a (Cell division cycle 25 A) inhibitors, CDC 25c (Cell division cycle 25 C) inhibitors, and DNA-PK (DNA-dependent protein kinase) inhibitors One or more selected from the group can be mentioned. The inhibitor may be one that can inhibit the function of a plurality of types of proteins. The above-mentioned inhibitor has, for example, (i) an inhibitor having both a function as an ATM inhibitor and a function as an ATR inhibitor, and (ii) a function as a CHK1 inhibitor and a function as a WEE1 inhibitor. It may be an inhibitor, an inhibitor having both a function as a CHK1 inhibitor and a function as a CHK2 inhibitor.

The above-mentioned inhibitor includes a compound containing a monoprime ring in the structure, a compound containing a heterocyclic ring in the structure, a compound containing both a monoprime ring and a heterocyclic ring in the structure, and a compound in the structure. It may be one or more selected from the group consisting of compounds containing an amide bond.

The types of elements constituting the monoprime ring are not particularly limited. From the viewpoint of achieving a higher desired effect, it is preferable that the monoprime ring is formed only of carbon. Further, the types of elements constituting the heterocyclic ring are not particularly limited. From the perspective of achieving higher desired effects, the heterocycle is formed solely of (i) carbon and (ii) at least one selected from the group consisting of sulfur, nitrogen and oxygen. Is preferable. The number of elements constituting the single ring and the heterocycle is not particularly limited. From the viewpoint of achieving a higher desired effect, the monoelemental ring and the heterocyclic ring are formed of 3 to 20 elements, 3 to 15 elements, or 3 to 10 elements. Is preferable.

In the case of a compound having an amide bond, the number of amide bonds contained in the compound is not particularly limited. From the viewpoint of achieving a higher desired effect, the number of amide bonds contained in the compound is preferably 1 to 10, and more preferably 1 to 5.

The details of each inhibitor will be further described below.

As used herein, the term "PLK3 inhibitor" is intended to be a substance that inhibits the function of PLK3. At this time, the PLK3 may be derived from a human or a non-human organism (for example, a non-human mammal). For example, PLK3 has an amino acid level identity of preferably 90% or more, more preferably 92% or more, more preferably 95% or more, and most preferably 98% or more, as compared with human-derived PLK3. possible. The PLK3 inhibitor may be one that inhibits the function of PLK3 "directly" by binding to PLK3, or "indirectly" by capturing a substance necessary for the function of PLK3. It may be one that inhibits the function of PLK3.

As a specific example of the PLK3 inhibitor, GW843682X (IUPAC name: 5- (5,6-dimethoxy-1H-benzimidazole-1-yl) -3-{[2- (trifluoromethyl) -benzyl] oxy} thiophene-2- carboxamide), TC-S7005 (IUPAC name: 3- (1,3-Benzodioxol-5-yl) -N-[(1S) -1-phenylethyl] -isoxazolo [5,4-c] pyridin-5-amine) , BI2536 (IUPAC name: (R) -4-((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl) amino) -3-methoxy) -N- (1-methylpiperidin-4-yl) benzamide), and derivatives or salts thereof. Of course, the present invention is not limited to these specific examples.

As used herein, the term "ATM inhibitor" is intended to be a substance that inhibits the function of ATM. At this time, the ATM may be derived from a human or a non-human organism (for example, a non-human mammal). For example, ATMs have an amino acid level identity of preferably 90% or higher, more preferably 92% or higher, more preferably 95% or higher, and most preferably 98% or higher, as compared to human-derived ATMs. possible. The ATM inhibitor may be one that "directly" inhibits the function of the ATM by binding to the ATM, or "indirectly" by capturing a substance necessary for the function of the ATM. It may interfere with the function of the ATM.

Specific examples of ATM inhibitors include CGK733 (IUPAC name: 2,2-diphenyl-n-(2,2,2-trichloro-1-[3-(4-fluoro-3-nitrophenyl) thioureide] ethyl) acetamide. ), KU55933 (IUPAC name: 2- (4-Morpholinyl) -6- (1-thianthrenyl) -4H-Pyran-4-one, 2- (Morpholin-4-yl) -6- (thianthren-1-yl) -4H-pyran-4-one), CP466722 (IUPAC name: 2- (6,7-Dimethoxy-quinazolin-4-yl) -5-pyridin-2-yl-2H- [1,2,4] triazol- 3-ylamine), KU60019 (IUPAC name: 2-((2S, 6R) -2,6-dimethylmorpholino) -N- (5- (6-morpholino-4-oxo-4H-pyran-2-yl) -9H -thioxanthen-2-yl) acetamide), AZD0156 (IUPAC name: 8- [6- [3- (dimethylamino) propoxy] -3-pyridyl] -3-methyl-1-tetrahydropyran-4-yl-imidazo [4, 5-c] quinolin-2-one), Milin (IUPAC name: (5Z) -2-amino-5-[(4-hydroxyphenyl) methylidene] -1,3-thiazol-4-one), KU59403 (IUPAC name) : 3- (4-methylpiperazin-1-yl) -N- (6- (6-morpholino-4-oxo-4H-pyran-2-yl) thianthren-2-yl) propanamide), Torin2 (IUPAC name: 9) -(6-aminopyridin-3-yl) -1- [3- (trifluoromethyl) phenyl] benzo [h] [1,6] naphthyridin-2-one), Caffeine (IUPAC name: 1,3,7-Trimethylpurine- 2,6-dione), LY294002 (IUPAC name: 2-morpholin-4-yl-8-phenylchromen-4-one), Wortmannin (IUPAC name: (1S, 6bR, 9aS) , 11R, 11bR) -1- (Methoxymethyl) -9a, 11b-dimethyl-3,6,9-trioxo-1,6,6b, 7,8,9,9a, 10,11,11b-decahydro-3H- furo [4,3,2-de] indeno [4,5-h] isochromen-11-yl acetate), and derivatives or salts thereof. Of course, the present invention is not limited to these specific examples.

As used herein, the term "ATR inhibitor" is intended to be a substance that inhibits the function of ATR. At this time, the ATR may be of human origin or may be of non-human organisms (eg, non-human mammals). For example, ATRs have an amino acid level identity of preferably 90% or higher, more preferably 92% or higher, more preferably 95% or higher, and most preferably 98% or higher, as compared to human-derived ATR. possible. The ATR inhibitor may be one that "directly" inhibits the function of ATR by binding to ATR, or "indirectly" by capturing a substance necessary for the function of ATR. It may be one that inhibits the function of ATR.

Specific examples of ATR inhibitors include CGK733 (IUPAC name: 2,2-diphenyl-n-(2,2,2-trichloro-1-[3-(4-fluoro-3-nitrophenyl) thioureide] ethyl) acetamide. ), VE-821 (IUPAC name: 3-Amino-6- (4- (methylsulfonyl) phenyl) -N-phenylpyrazine-2-carboxamide, 3-Amino-6- [4- (methylsulfonyl) phenyl] -N-phenyl -2-pyrazinecarboxamide), DACTORISIB (IUPAC name: 2-methyl-2- (4- (3-methyl-2-oxo-8- (quinolin-3-yl) -2,3-dihydroimidazo [4,5-c] ] quinolin-1-yl) phenyl) propanenitrile), AZD6738 (IUPAC name: 4- [4- [1-[[S (R)]-S-methylsulfonimidoyl] cyclopropyl] -6-[(3R) -3-methyl -4-morpholinyl] -2-pyrimidinyl] -1H-pyrrolo [2,3-b] pyridine), VE-822 (IUPAC name: 5- (4- (isopropylsulfonyl) phenyl) -3- (3- (4- (4-) ((methylamino) methyl) phenyl) isoxazol-5-yl) pyrazin-2-amine), AZ-20 (IUPAC name: (R) -4- (2- (1H-indol-4-yl) -6- ( 1- (methylsulfonyl) cyclopropyl) pyrimidin-4-yl) -3-methylmorpholine), Torin2 (IUPAC name: 9- (6-aminopyridin-3-yl) -1- [3- (trifluoromethyl) phenyl] benzo [h] [1,6] naphthyridin-2-one), Cafeine (IUPAC name: 1,3,7-Trimethylpurine-2,6-dione), LY294002 (IUPAC name: 2-morpholin-4-yl-8-phenylchromen-4) -one), Wortmannin (IUPAC name: (1S, 6bR, 9aS, 11R, 1) 1bR) -1- (Methoxymethyl) -9a, 11b-dimethyl-3,6,9-trioxo-1,6,6b, 7,8,9,9a, 10,11,11b-decahydro-3H-furo [4 , 3,2-de] indeno [4,5-h] isochromen-11-yl acetate), Scientificin B (IUPAC name: (6R, 7S) -1,2,3,13-Tetramethoxy-6,7-dimethyl -5,6,7,8-tetrahydrobenzo [3', 4'] cycloocta [1', 2': 4,5] benzo [1,2-d] [1,3] dioxole), NU6027 (IUPAC name:: 4-{[4-Amino-6- (cyclohexylmethoxy) -5-nitroso-2-pyrimidinyl] amino} benzamide), NVP-BEZ235 (IUPAC name: 2-Methyl-2- {4- [3-methyl-2-] oxo-8- (quinolin-3-yl) -2,3-dihydro-1H-imidazo [4,5-c] quinolin-1-yl] phenyl} propanenitrile), ETP46464 (IUPAC name: 2-methyl-2- {4- [2-oxo-9- (quinolin-3-yl) -4H- [1,3] oxazino [5,4-c] quinolin-1-yl] phenyl} propanenitrile), and derivatives of these or Salt, can be mentioned. Of course, the present invention is not limited to these specific examples.

As used herein, the term "p53 inhibitor" is intended to be a substance that inhibits the function of p53. At this time, p53 may be of human origin or may be of non-human organisms (eg, non-human mammals). For example, p53 has an amino acid level identity of preferably 90% or higher, more preferably 92% or higher, more preferably 95% or higher, and most preferably 98% or higher, as compared to human-derived p53. possible. The p53 inhibitor may be one that "directly" inhibits the function of p53, such as by binding to p53, or "indirectly" by capturing a substance necessary for the function of p53. It may be one that inhibits the function of p53.

Specific examples of the p53 inhibitor include PFTα (IUPAC name: 2- (2-imino-4,5,6,7-tetrahydrobenzothiazole-3-yl) -1-p-tolylethanone hydrobromide), Pifithrin-μ (IUPAC name). : 2-Phenylacetylenesulfonamide), Nutlin-3 (IUPAC name: 4-{[(4R, 5S) -4,5-Bis (4-chlorophenyl) -2- (2-isopropoxy-4-methoxyphenyl) -4,5- dihydro-1H-imidazol-1-yl] carbonyl} -2-piperazinone), Ellipticine (IUPAC name: 5,11-Dimethyl-6H-pyrido [4,3-b] carbazole), Roscovitine (IUPAC name: (2R)) -2-{[6- (Benzylamino) -9-isopropyl-9H-purin-2-yl] amino} -1-butanol), Pifithrin-α (IUPAC name: 2-Amino-3- [2- (4- (4- (4-) methylphenyl) -2-oxoethyl] -2,3,4,5,6,7-hexahydro-1,3-benzothiazol-2-ylium bromide), 9-Hydroxyllipticine (IUPAC name: 5,11-Dimethyl-6H-pyrido) [4,3-b] carbazol-9-ol hydrochloride), Cyclic Pifithrin-α hydroxybromide (IUPAC name: 4- (4-methylphenyl) -7-thia-2,5-diazatricyclo [6.4.0.0 ² , ⁶ ] dodeca -1 (8), 3,5-triene hydrobromide), SJ 172550 (IUPAC name: Methyl 2- (2-chloro-6-ethoxy-4-((3-methyl-5-oxo-1-phenyl-1H-) Pyrazol-4 (5H) -ylidene) methyl) phenoxy) acetate), and derivatives or salts thereof. Of course, the present invention is not limited to these specific examples.

As used herein, the term "CHK1 inhibitor" is intended to be a substance that inhibits the function of CHK1. At this time, CHK1 may be derived from a human or a non-human organism (for example, a non-human mammal). For example, CHK1 has an amino acid level identity of preferably 90% or higher, more preferably 92% or higher, more preferably 95% or higher, and most preferably 98% or higher, as compared to human-derived CHK1. possible. The CHK1 inhibitor may be one that "directly" inhibits the function of CHK1 by binding to CHK1 or the like, or "indirectly" by capturing a substance necessary for the function of CHK1. It may be one that inhibits the function of CHK1.

Specific examples of the CHK1 inhibitor include PD407824 (IUPAC name: 9-Hydroxy-4-phenylpyrrolo [3,4-c] carbazole-1,3 (2H, 6H) -dione) and AZD7762 (IUPAC name: 5-( 3-Fluorophenyl) -3-ureidothiophene-2-carboxylic acid N-[(S) -piperidin-3-yl] amide hydrochloride), CHIR-124 (IUPAC name: (S) -3- (1H-benzo [d]] imidazol-2-yl) -6-chloro-4- (quinuclidin-3-ylamino) quinolin-2 (1H) -one), LY2603618 (IUPAC name: (S) -1- (5-bromo-4-methyl-) 2- (morpholin-2-ylmethoxy) phenyl) -3- (5-methylpyrazin-2-yl) urea), UCN01 (IUPAC name: (9S, 10R, 11R, 13R) -2,3,10,11,12 , 13-Hexahydro-10-methoxy-9-methyl-11-(methylamino) -9,13-epoxy-1H, 9H-diindolo [1,2,3-gh: 3', 2', 1'-lm] pyrrolo [3,4-j] [1,7] benzodiazonin-1-one), MK8776 (IUPAC name: 6-bromo-3- (1-methylpyrazol-4-yl) -5-[(3R) -piperidin- 3-yl] pyrazolo [1,5-a] pyrimidin-7-amine), PF477736 (IUPAC name: (R) -2-Amino-2-cyclohexyl-N- [2- (1-methyl-1H-pyrazol-) 4-yl) -6-oxo-5,6-dihydro-1H- [1,2] diazepino [4,5,6-cd] indol-8-yl] -acetamide), SB218578 (IUPAC name: 9,10) , 11,12-Tetrahydro-9,12-epoxy-1H-diindolo [1,2,3-fg: 3', 2', 1'-kl] pyrrolo [3,4-i] [1,6] benzodiazocine -1,3 (2H) -dione), TCS2312 (IUPAC name: 4'-[5-[[3-[(Cyc) lopropylamino) methyl] phenyl] amino] -1H-pyrazol-3-yl]-[1,1'-biphenyl] -2,4-diol), and derivatives or salts thereof. Of course, the present invention is not limited to these specific examples.

As used herein, the term "CHK2 inhibitor" is intended to be a substance that inhibits the function of CHK2. At this time, CHK2 may be of human origin or may be of non-human organisms (eg, non-human mammals). For example, CHK2 has an amino acid level identity of preferably 90% or higher, more preferably 92% or higher, more preferably 95% or higher, and most preferably 98% or higher, as compared to human-derived CHK2. possible. The CHK2 inhibitor may be one that "directly" inhibits the function of CHK2 by binding to CHK2, or "indirectly" by capturing a substance necessary for the function of CHK2. It may be one that inhibits the function of CHK2.

Specific examples of the CHK2 inhibitor include AZD7762 (IUPAC name: 5- (3-Fluorophenyl) -3-ureidothiophene-2-carboxylic acid N-[(S) -piperidin-3-yl] amide hydrochloride), Chk2 inhibitor II. (IUPAC name: 2- (4- (4-Chlorophenoxy) phenyl) -1H-benzimidazole-5-carboxamide hydrate), CCT241533 (IUPAC name: (3R, 4S) -4-[[2- (5-Fluoro-2) -hydroxyphenyl) -6,7-dimethoxy-4-quinazolinyl] amino] -α, α-dimethyl-3-pyrrolidinemethanol dihydrochloride), PV1019 (IUPAC name: 7-nitro-1H-indole-2-carboxylic acid {4- [ 1- (guanidinohydrazone) -ethyl] -phenyl} -amide), Debromohymenialdisine (IUPAC name: (4Z) -4- (2-Amino-5-oxo-1,5-dihydro-4H-imidazol-4-ylidene)- 4,5,6,7-tetrahydropyrrolo [2,3-c] azepin-8 (1H) -one), VRX04666617 (IUPAC name: 5- [4- (4-Bromoanilino) anilino]-N'-(1-) hydroxypropan-2-yl) -3-oxo-1,2-thiazole-4-carboximidamide), and derivatives or salts thereof. Of course, the present invention is not limited to these specific examples.

As used herein, the term "WEE1 inhibitor" is intended to be a substance that inhibits the function of WEE1. At this time, WEE1 may be derived from a human or a non-human organism (for example, a non-human mammal). For example, WEE1 has an amino acid level identity of preferably 90% or more, more preferably 92% or more, more preferably 95% or more, and most preferably 98% or more, as compared with human-derived WEE1. possible. The WEE1 inhibitor may be one that "directly" inhibits the function of WEE1 by binding to WEE1 or the like, or "indirectly" by capturing a substance necessary for the function of WEE1. It may be one that inhibits the function of WEE1.

Specific examples of the WEE1 inhibitor include PD407824 (IUPAC name: 9-Hydroxy-4-phenylpyrrolo [3,4-c] carbazole-1,3 (2H, 6H) -dione) and MK1775 (IUPAC name: 2-allyl). -1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -6- (4- (4-methylpiperazin-1-yl) phenylamino) -1,2-dihydropyrazolo [3,4-d ] Pyrimidin-3-one), and derivatives or salts thereof. Of course, the present invention is not limited to these specific examples.

As used herein, the term "PLK1 inhibitor" is intended to be a substance that inhibits the function of PLK1. At this time, PLK1 may be derived from a human or a non-human organism (for example, a non-human mammal). For example, PLK1 has an amino acid level identity of preferably 90% or higher, more preferably 92% or higher, more preferably 95% or higher, and most preferably 98% or higher, as compared to human-derived PLK1. possible. The PLK1 inhibitor may be one that "directly" inhibits the function of PLK1 by binding to PLK1 or the like, or "indirectly" by capturing a substance necessary for the function of PLK1. It may be one that inhibits the function of PLK1.

Specific examples of the PLK1 inhibitor include BI2536 (IUPAC name: (R) -4-((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-)). yl) amino) -3-methoxy-N- (1-methylpiperidin-4-yl) benzamide), VOLASERTIB (IUPAC name: N-((1r, 4r) -4- (4- (cyclopropylmethyl) piperazin-1-yl) ) Cyclohexyl) -4-((R) -7-ethyl-8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-ylamino) -3-methoxybenzamide), GSK461364 (IUPAC) Name: 5- (6-((4-methylpiperazin-1-yl) methyl) -1H-benzo [d] imidazol-1-yl) -3-((R) -1- (2- (trifluoromethyl) phenyl) ethoxy) thiophene-2-carboxamide), and derivatives or salts thereof. Of course, the present invention is not limited to these specific examples.

As used herein, the term "aurora A kinase inhibitor inhibitor" is intended to be a substance that inhibits the function of an aurora A kinase inhibitor. At this time, the Aurora A kinase inhibitor may be derived from a human or a non-human organism (for example, a non-human mammal). For example, an Aurora A kinase inhibitor is preferably 90% or more, more preferably 92% or more, more preferably 95% or more, and most preferably 98% or more amino acids as compared with a human-derived Aurora A kinase inhibitor. It can have a level of identity. The aurora A kinase inhibitor inhibitor may be one that "directly" inhibits the function of the aurora A kinase inhibitor, such as by binding to the aurora A kinase inhibitor, or the aurora A kinase inhibitor. It may be one that "indirectly" inhibits the function of the Aurora A kinase inhibitor, such as by capturing a substance required for its function.

Specific examples of the aurora A kinase inhibitor inhibitor include MLN8237 (IUPAC name: 4-{[9-Chloro-7- (2-fluoro-6-methoxyphenyl) -5H-pyrimido [5,4-d] [2]. ] benzazepin-2-yl] amino} -2-methoxybenzoic acid), AURORA A INHIBITOR I (IUPAC name: N- (2-chlorophenyl) -4- (2- (4- (2- (4-ethylpiperazin-1-) yl) -2-oxoethyl) phenylamino) -5-fluoropyrimidin-4-ylamino) benzamide), and derivatives or salts thereof. Of course, the present invention is not limited to these specific examples.

As used herein, the term "DNA replication inhibitor" is intended to be a substance that prevents any one of a plurality of steps for replicating DNA (specifically, chromosomal DNA) from being performed. A DNA replication inhibitor may be one that "directly" inhibits the function of the protein, such as by binding to any of a plurality of proteins required to replicate the DNA, or it replicates the DNA. It may be one that "indirectly" inhibits the function of the protein, such as by capturing a substance necessary for the function of any of the plurality of proteins necessary for the above.

Specific examples of the DNA replication inhibitor include Etoposide (IUPAC name: 4'-dimethylepipodophyllotoxin 9- (4,6-O-ethylidene-β-D-glucopyranoside)) and ELLIPTICINE (IUPAC name: 5,11-Dimethyl-6H). -pyrido [4,3-b] carbazole), and derivatives or salts thereof. Of course, the present invention is not limited to these specific examples.

As used herein, the term "DNA synthesis inhibitor" is intended to be a substance that prevents any of a plurality of steps for synthesizing DNA (specifically, chromosomal DNA) from being performed. The DNA synthesis inhibitor may be one that "directly" inhibits the function of the protein by binding to any of a plurality of proteins necessary for synthesizing DNA, or synthesizes DNA. It may be one that "indirectly" inhibits the function of the protein, such as by capturing a substance necessary for the function of any of the plurality of proteins necessary for the protein.

Specific examples of the DNA synthesis inhibitor include HU (IUPAC name: Hydroxycarbamide), 5-FU (IUPAC name: 5-Fluorouracil), and derivatives or salts thereof. Of course, the present invention is not limited to these specific examples.

As used herein, the term "mitotic inhibitor" is intended to be a substance that prevents any one of a plurality of steps for performing mitosis from being performed. The mitotic inhibitor may be one that "directly" inhibits the function of the protein by binding to any of a plurality of proteins required for mitosis, or it may cause mitosis. It may be one that "indirectly" inhibits the function of the protein, such as by capturing a substance necessary for the function of any of the plurality of proteins required.

Specific examples of mitotic inhibitors include Taxol (IUPAC name: (2α, 4α, 5β, 7β, 10β, 13α) -4,10-bis (acetyloxy) -13-{[(2R, 3S) -3). -(Benzoylamino) -2-hydroxy-3-phenylpropanoyl] oxy} -1,7-dihydroxy-9-oxo-5,20-epoxytax-11-en-2-yl benzoate), NOCODAZOLE (IUPAC name: Methyl [5) -(2-thienylcarbonyl) -1H-benzimidazol-2-yl] carbamate), and derivatives or salts thereof. Of course, the present invention is not limited to these specific examples.

As used herein, the term "CDC25a inhibitor" is intended to be a substance that inhibits the function of CDC25a. At this time, the CDC 25a may be derived from a human or a non-human organism (for example, a non-human mammal). For example, the CDC25a has an amino acid level identity of preferably 90% or more, more preferably 92% or more, more preferably 95% or more, and most preferably 98% or more, as compared with a human-derived CDC25a. possible. The CDC25a inhibitor may be one that "directly" inhibits the function of the CDC25a by binding to the CDC25a, or "indirectly" by capturing a substance necessary for the function of the CDC25a. It may be one that inhibits the function of CDC 25a.

Specific examples of the CDC25a inhibitor include PM-20 (IUPAC name: 1- [1,1'-Biphenyl] -4-yl-3,4-bis [(2-hydroxyethyl) thio] -1H-Pyrrole-2. , 5-dione), NSC95397 (IUPAC name: 2,3-bis [(2-Hydroxyethyl) thiol] -1,4-naphthoquinone), NSC663284 (IUPAC name: 6-Chloro-7-[[2- (4-) morpholinyl) ethyl] amino] -5,8-quinolinedione), K-252a (IUPAC name: (9S- (9α, 10β, 12α))-2,3,9,10,11,12-hexahydro-10-hydroxy -10-(methoxycarbonyl) -9-methyl-9,12-epoxy-1H-diindolo [1,2,3-fg: 3', 2', 1'-kl] pyrrolo [3,4-i] [1 , 6] benzodiazocin-1-one), CDC25 Phosphace Inhibitor I, BN82002 (IUPAC name: 4- (dimethylamino) -2-methoxy-6- [[methyl- [2- (4-nitrophenyl) ethyl] amino] methyl] phenol), and derivatives or salts thereof. Of course, the present invention is not limited to these specific examples.

As used herein, the term "CDC25c inhibitor" is intended to be a substance that inhibits the function of CDC25c. At this time, the CDC25c may be of human origin or may be of non-human organisms (eg, non-human mammals). For example, CDC25c has an amino acid level identity of preferably 90% or higher, more preferably 92% or higher, more preferably 95% or higher, and most preferably 98% or higher, as compared to human-derived CDC25c. possible. The CDC25c inhibitor may be one that "directly" inhibits the function of the CDC25c, such as by binding to the CDC25c, or "indirectly" by capturing a substance necessary for the function of the CDC25c. It may be one that inhibits the function of CDC25c.

Specific examples of the CDC25c inhibitor include NSC95397 (IUPAC name: 2,3-bis [(2-Hydroxyethyl) thiol] -1,4-naphthoquinone) and NSC663284 (IUPAC name: 6-Chloro-7-[[2-]. (4-morpholinyl) ethyl] amino] -5,8-quinolinedione), K-252a (IUPAC name: (9S- (9α, 10β, 12α))-2,3,9,10,11,12-hexahydro- 10-hydroxy-10- (methoxycarbonyl) -9-methyl-9,12-epoxy-1H-diindolo [1,2,3-fg: 3', 2', 1'-kl] pyrrolo [3,4-i ] [1,6] benzodiazocin-1-one), CDC25 Phosphace Inhibitor I, BN82002 (IUPAC name: 4- (dimethylamino) -2-methoxy-6-[[methyl- [2- (4-nitrophenyl) ethyl] amino ] Methyl] phenol), mpV (pic) (IUPAC name: hydrogen peroxide; 5-hydroxypyridine-2-carboxylic acid; oxovanadium), and derivatives or salts thereof. Of course, the present invention is not limited to these specific examples.

As used herein, the term "DNA-PK inhibitor" is intended to be a substance that inhibits the function of DNA-PK. At this time, the DNA-PK may be derived from a human or a non-human organism (for example, a non-human mammal). For example, DNA-PK has an amino acid level identity of preferably 90% or higher, more preferably 92% or higher, more preferably 95% or higher, and most preferably 98% or higher, as compared to human-derived DNA-PK. Can have. The DNA-PK inhibitor may be one that "directly" inhibits the function of DNA-PK, such as by binding to DNA-PK, or captures substances necessary for the function of DNA-PK. For example, it may be one that "indirectly" inhibits the function of DNA-PK.

Specific examples of the DNA-PK inhibitor include PIK-75 HCL (IUPAC name: (E) -N'-((6-bromoH-imidazo [1,2-a] pyridin-3-yl) methylene) -N. , 2-dimethyl-5-nitrobenzenesulfonohydrazide hydrochloride), NU7441 (IUPAC name: 8- (4-Dibenzothienyl) -2- (4-morpholinyl) -4H-1-benzopyran-4-one), PI-103 (IUPAC name:: 3- (4-Morpholin-4-ylpyrido [2,3] furo [2,4-b] pyrimidin-2-yl) phenol), NU9056 (IUPAC name: 2-morpholin-4-ylbenzo [h] chromen-4 -one), KU-0060648 (IUPAC name: 2- (4-ethylpiperazin-1-yl) -N- [4- (2-morpholin-4-yl-4-oxochromen-8-yl) dibenzothiophen-1-yl ] acetamide), CC-115 (IUPAC name: 1-ethyl-7- (2-methyl-6- (1H-1,2,4-triazol-5-yl) pyridin-3-yl) -3,4- dihydropyrazino [2,3-b] pyrazin-2 (1H) -one), DMNB (IUPAC name: 2,3-Dimethyl-2,3-dinitrobutane), IC86621 (IUPAC name: 1- [2-hydroxy-4-] (morpholin-4-yl) phenyl] ethan-1-one), DNA-PK inhibitor V (IUPAC name: 2-benzoyl-5- (morpholin-4-yl) phenol), and derivatives or salts thereof. Can be mentioned. Of course, the present invention is not limited to these specific examples.

The structures of typical examples of the above-mentioned inhibitors are described below. However, the invention is not limited to these inhibitors.

In the inhibitor of one embodiment, a derivative or salt of the above-mentioned substance may be used. By using a derivative or salt of the above-mentioned substance, (1) the preventive effect and / or the therapeutic effect of cataract can be increased, (2) the safety of the substance to the human body can be increased, and (3) an easy-to-use substance can be used. It is possible to obtain effects such as being able to formulate.

As used herein, the term "derivative" is intended for a group of compounds resulting from the substitution of a portion of the compound in the molecule with another functional group or other atom for a particular compound.

Examples of the above other functional groups include an alkyl group, an alkoxy group, an alkylthio group, an aryl group, an aryloxy group, an arylthio group, an arylalkyl group, an arylalkoxy group, an arylalkylthio group, an arylalkenyl group, an arylalkynyl group and an allyl. Examples thereof include a group, an amino group, a substituted amino group, a silyl group, a substituted silyl group, a silyloxy group, a substituted silyloxy group, an arylsulphonyloxy group, an alkylsulphonyloxy group, a nitro group and the like. Examples of the above other atoms include a carbon atom, a hydrogen atom, an oxygen atom, a nitrogen atom, a sulfur atom, a phosphorus atom, a halogen atom and the like.

As used herein, the term "salt" is intended to be a salt that is physiologically acceptable to be administered to a subject. Examples of salts include alkali metal salts (potassium salt, etc.), alkaline earth metal salts (calcium salt, magnesium salt, etc.), ammonium salts, organic base salts (trimethylamine salt, triethylamine salt, pyridine salt, picolin salt, dicyclohexylamine). Salts, N, N'-dibenzylethylenediamine salts, etc.), organic acid salts (acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, nitate, toluenesulfonate, trifluoroacetate, etc.) Etc.), inorganic acid salts (salts, hydrobromide, sulfates, phosphates, etc.).

The above-mentioned inhibitor can be produced according to a known method. Further, as the above-mentioned inhibitor, a commercially available one can also be used.

[4. Cataract prophylaxis or treatment]
The preventive or therapeutic agent for cataract according to one embodiment of the present invention contains, as an active ingredient, an inhibitor that inhibits the signal transduction pathway in response to the above-mentioned DNA damage. Hereinafter, the preventive or therapeutic agent for cataract of the present embodiment will be described.

[4-1. Dosage form and dosage form]
The preventive or therapeutic agent for cataract according to one embodiment of the present invention is administered to a subject. In one embodiment, the subject is a human. In other embodiments, the subject is a non-human animal. Examples of the non-human animals include non-human mammals (cattle, pigs, sheep, goats, horses, dogs, cats, rabbits, mice, rats, etc.).

The prophylactic or therapeutic agent for cataract according to one embodiment of the present invention can be administered to a subject by any route of administration. Examples of the above-mentioned administration route include oral administration, parenteral administration, transdermal administration, transmucosal administration, and intravenous administration. Therefore, the dosage form of the preventive or therapeutic agent for cataract may be an internal medicine, an external medicine, an injection, a suppository, an inhaler, an eye drop, or the like.

Among the above-mentioned administration routes, parenteral administration is preferable, eye drop administration, intravitreal administration, intravitreal administration, subconjunctival administration, and subconjunctival administration are more preferable, and eye drop administration is further preferable. Therefore, among the above-mentioned dosage forms, eye drops or injections are preferable, and eye drops are more preferable. The reasons why eye drops are preferable are that the route to deliver the active ingredient to the crystalline lens is short, it is difficult to stimulate other organs, there is almost no invasion, and the effect on the whole body is small (punctum after instillation). The effect on the whole body can be further suppressed by compression), administration is easy, repeated administration is possible, and the patient can self-manage. With the above configuration, it can be expected that the preventive or therapeutic effect of cataract can be made more rapid or increased.

[4-2. Ingredients]
The preventive or therapeutic agent for cataract according to one embodiment of the present invention contains, as an active ingredient, an inhibitor that inhibits a signal transduction pathway in response to DNA damage. As used herein, the term "active ingredient" is intended to be a substance capable of producing a prophylactic or therapeutic effect on one or more symptoms.

The concentration of the inhibitor contained in the preventive or therapeutic agent for cataract according to the embodiment of the present invention depends on the type of the inhibitor, the administration route of the preventive agent or the therapeutic agent, the dosage form of the preventive agent or the therapeutic agent, and the like. Can be different.

In one example, the lower limit of the concentration of the inhibitor in the prophylactic or therapeutic agent is 0.001 μM or more, 0.002 μM or more, 0.005 μM or more, 0.01 μM or more, 0.02 μM or more, 0.05 μM or more, 0.1 μM. 0.2 μM or more, 0.5 μM or more, 1 μM or more, 2 μM or more, 3 μM or more, 4 μM or more, 5 μM or more, 6 μM or more, 7 μM or more, 8 μM or more, 9 μM or more, 10 μM or more, 20 μM or more, 30 μM or more, 40 μM or more. , 50 μM or more, 60 μM or more, 70 μM or more, 80 μM or more, 90 μM or more, 100 μM or more, 200 μM or more, 300 μM or more, 400 μM or more, 500 μM or more, or 1000 μM or more.

In one example, the upper limit of the concentration of the inhibitor in the prophylactic or therapeutic agent is 0.01 μM or less, 0.02 μM or less, 0.05 μM or less, 0.1 μM or less, 0.2 μM or less, 0.5 μM or less, 1 μM or less, 2 μM or less, 3 μM or less, 4 μM or less, 5 μM or less, 6 μM or less, 7 μM or less, 8 μM or less, 9 μM or less, 10 μM or less, 20 μM or less, 30 μM or less, 40 μM or less, 50 μM or less, 60 μM or less, 70 μM or less, 80 μM or less, 90 μM or less. , 100 μM or less, 200 μM or less, 300 μM or less, 400 μM or less, 500 μM or less, 1000 μM or less, 2000 μM or less, or 5000 μM or less.

In one example, the concentrations of the inhibitor in the prophylactic or therapeutic agent are 0.001 μM to 5000 μM, 0.001 to 0.01 μM, 0.002 to 0.02 μM, 0.005 to 0.05 μM, 0.01 to 0.01. 0.1 μM, 0.02 to 0.2 μM, 0.05 to 0.5 μM, 0.1 to 1 μM, 0.2 to 2 μM, 0.3 to 3 μM, 0.4 to 4 μM, 0.5 to 5 μM, 0.6 to 6 μM, 0.7 to 7 μM, 0.8 to 8 μM, 0.9 to 9 μM, 1 to 10 μM, 2 to 20 μM, 3 to 30 μM, 4 to 40 μM, 5 to 50 μM, 6 to 60 μM, 7 to 70 μM, 8-80 μM, 9-90 μM, 10-100 μM, 20-200 μM, 30-300 μM, 40-400 μM, 50-500 μM, 60-600 μM, 70-700 μM, 80-800 μM, 90-900 μM, 100-1000 μM, It is 200 to 2000 μM or 500 to 5000 μM.

The preventive or therapeutic agent for cataract according to one embodiment of the present invention may contain a component other than the inhibitor.

Ingredients other than the above inhibitors include buffers, pH regulators, tonicity agents, preservatives, antioxidants, high molecular weight polymers, excipients, carriers, diluents, solvents, solubilizers, stabilizers. , Fillers, binders, surfactants, stabilizers and the like.

Examples of the above buffers are phosphate, phosphate, borate, borate, citric acid, citrate, acetic acid, acetate, carbonate, carbonate, tartrate, tartrate, ε-aminocaproic acid, and , Trometa mall, etc. Examples of the phosphate include sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate and the like. Examples of the borate include borax, sodium borate, potassium borate and the like. Examples of the citrate include sodium citrate, disodium citrate, trisodium citrate and the like. Examples of the acetate include sodium acetate, potassium acetate and the like. Examples of the carbonate include sodium carbonate and sodium hydrogen carbonate. Examples of the tartrate salt include sodium tartrate and potassium tartrate.

Examples of the pH adjuster include hydrochloric acid, phosphoric acid, citric acid, acetic acid, sodium hydroxide, potassium hydroxide and the like.

Examples of the above isotonic agents include ionic isotonic agents (sodium chloride, potassium chloride, calcium chloride, magnesium chloride, etc.) and nonionic isotonic agents (glycerin, propylene glycol, sorbitol, etc.). And mannitol etc.).

Examples of the preservatives include benzalkonium chloride, benzalkonium bromide, benzethonium chloride, sorbic acid, potassium sorbate, methyl paraoxybenzoate, propyl paraoxybenzoate, and chlorobutanol.

Examples of the antioxidant include ascorbic acid, tocophenol, dibutylhydroxytoluene, butylhydroxyanisole, sodium erythorbate, propyl gallate, sodium sulfite and the like.

Examples of the high molecular weight polymer include methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropylmethyl cellulose acetate succinate, and hydroxypropyl methyl cellulose phthalate. , Carboxymethylethyl cellulose, cellulose acetate phthalate, polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, polyethylene glycol, atelocollagen and the like.

In particular, if the preventive or therapeutic agent for cataract according to one embodiment of the present invention contains atelocollagen, the absorption rate of the inhibitor increases, which is preferable.

The concentration of the component other than the inhibitor contained in the preventive agent or the therapeutic agent for cataract according to the embodiment of the present invention is not particularly limited, and for example, the concentration of the component other than the above-mentioned inhibitor in the preventive agent or the therapeutic agent is not particularly limited. 0 μM, 0.001 μM to 5000 μM, 0.001 to 0.01 μM, 0.002 to 0.02 μM, 0.005 to 0.05 μM, 0.01 to 0.1 μM, 0.02 to 0.2 μM, 0. 05 to 0.5 μM, 0.1 to 1 μM, 0.2 to 2 μM, 0.3 to 3 μM, 0.4 to 4 μM, 0.5 to 5 μM, 0.6 to 6 μM, 0.7 to 7 μM, 0. 8-8 μM, 0.9-9 μM, 1-10 μM, 2-20 μM, 3-30 μM, 4-40 μM, 5-50 μM, 6-60 μM, 7-70 μM, 8-80 μM, 9-90 μM, 10-100 μM, It may be 20 to 200 μM, 30 to 300 μM, 40 to 400 μM, 50 to 500 μM, 60 to 600 μM, 70 to 700 μM, 80 to 800 μM, 90 to 900 μM, 100 to 1000 μM, 200 to 2000 μM, or 500 to 5000 μM. ..

[4-3. Formulations and prescriptions]
A prophylactic or therapeutic agent for cataract according to an embodiment of the present invention can be formulated by a known method using the above-mentioned inhibitor and a component other than the above-mentioned inhibitor as raw materials.

When a prophylactic or therapeutic agent for cataract according to an embodiment of the present invention is administered (for example, when it is administered as an eye drop), there is no limitation on the administration interval as long as the desired effect can be obtained. The administration interval is, for example, once every 1 hour to 6 months, preferably once an hour, once every two hours, once every three hours, once every six hours, once every 12 hours. Once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, 3 Once a week, once a month, once every two months, once every three months, once every four months, once every five months, once every six months, and more. Preferably at least once a day, at least once every two days, at least once every three days, at least once every four days, at least once every five days, at least once every six days, at least once a week. Is.

A prophylactic or therapeutic agent for cataract according to an embodiment of the present invention may be prescribed in combination with an agent for preventing or treating cataract and / or other diseases.

Further, one aspect of the present invention is a method for preventing or treating cataract using a preventive or therapeutic agent for cataract containing an inhibitor that inhibits a signal transduction pathway in response to DNA damage as an active ingredient. In addition, one aspect of the present invention comprises a step of administering to a subject a preventive or therapeutic agent for cataract containing an inhibitor that inhibits a signal transduction pathway in response to DNA damage as an active ingredient. Method or treatment method.

In the following examples, the effect of each drug was tested using an ex vivo diabetic cataract model using a galactose-added medium.

<Example 1>
Lenses were removed from the left and right eyeballs of a 6-week-old SD rat (manufactured by Sankyo Lab Service). The crystalline lens removed from the right eye was cultured in M199 medium (manufactured by SIGMA) supplemented with 30 mM galactose. On the other hand, the crystalline lens removed from the left eye was cultured in M199 medium supplemented with 30 mM galactose and 1 μM PLK3 inhibitor (specifically, GW843682X).

An incubator was used for culturing each crystalline lens, and the temperature in the incubator was maintained at 37 ° C. Four days after the start of the culture, each crystalline lens was taken out from the medium and observed under a microscope using SZX12 (manufactured by Olympas).

The above tests were performed a total of 3 times.

FIG. 2 shows the test results of microscopic observation. As is clear from FIG. 2, in the crystalline lens excised from the right eye, which was cultured in a medium to which the PLK3 inhibitor was not added, the cortex became cloudy from the start of the culture to 4 days after the culture. .. On the other hand, in the crystalline lens excised from the left eye, which was cultured using the medium to which the PLK3 inhibitor was added, the white turbidity of the cortex was suppressed as compared with the crystalline lens excised from the right eye.

<Example 2>
Lenses were removed from the left and right eyeballs of a 6-week-old SD rat (manufactured by Sankyo Lab Service). The crystalline lens removed from the right eye was cultured in M199 medium (manufactured by SIGMA) supplemented with 30 mM galactose. On the other hand, the crystalline lens removed from the left eye was cultured using a medium in which 30 mM galactose and a 10 μM ATM and ATR inhibitor (specifically, CGK733) were added to M199 medium.

An incubator was used for culturing each crystalline lens, and the temperature in the incubator was maintained at 37 ° C. Four days after the start of the culture, each crystalline lens was taken out from the medium and observed under a microscope using SZX12 (manufactured by Olympas).

The above tests were performed a total of 3 times.

FIG. 3 shows the test results of microscopic observation. As is clear from FIG. 3, in the crystalline lens excised from the right eye, which was cultured in a medium to which no inhibitor of ATM and ATR was added, the cortex became cloudy from the start of the culture to 4 days after the culture. It was progressing. On the other hand, in the lens extracted from the left eye, which was cultured using the medium to which the inhibitor of ATM and ATR was added, the whitening of the cortex was suppressed as compared with the lens removed from the right eye. Was there.

<Example 3>
Lenses were removed from the left and right eyeballs of a 6-week-old SD rat (manufactured by Sankyo Lab Service). The crystalline lens removed from the right eye was cultured in M199 medium (manufactured by SIGMA) supplemented with 30 mM galactose. On the other hand, the crystalline lens removed from the left eye was cultured in M199 medium supplemented with 30 mM galactose and 20 μM ATR inhibitor (specifically, VE-821).

An incubator was used for culturing each crystalline lens, and the temperature in the incubator was maintained at 37 ° C. Four days after the start of the culture, each crystalline lens was taken out from the medium and observed under a microscope using SZX12 (manufactured by Olympas).

FIG. 4 shows the test results of microscopic observation. As is clear from FIG. 4, in the crystalline lens excised from the right eye, which was cultured in a medium to which no ATR inhibitor was added, the cortex became cloudy from the start of the culture to 4 days after the culture. .. On the other hand, in the crystalline lens excised from the left eye, which was cultured using the medium to which the ATR inhibitor was added, the white turbidity of the cortex was suppressed as compared with the crystalline lens excised from the right eye.

<Example 4>
Lenses were removed from the left and right eyeballs of a 6-week-old SD rat (manufactured by Sankyo Lab Service). The crystalline lens removed from the right eye was cultured in M199 medium (manufactured by SIGMA) supplemented with 30 mM galactose. On the other hand, the crystalline lens removed from the left eye was cultured in M199 medium supplemented with 30 mM galactose and 10 μM ATM inhibitor (specifically, KU55933).

An incubator was used for culturing each crystalline lens, and the temperature in the incubator was maintained at 37 ° C. Four days after the start of the culture, each crystalline lens was taken out from the medium and observed under a microscope using SZX12 (manufactured by Olympas).

FIG. 5 shows the test results of microscopic observation. As is clear from FIG. 5, in the crystalline lens excised from the right eye, which was cultured in a medium to which no ATM inhibitor was added, the cortex became cloudy from the start of the culture to 4 days after the culture. .. On the other hand, in the crystalline lens excised from the left eye, which was cultured using the medium to which the ATM inhibitor was added, the white turbidity of the cortex was suppressed as compared with the crystalline lens excised from the right eye.

<Example 5>
The crystalline lens was removed from the eyeball of a 6-week-old SD rat (manufactured by Sankyo Lab Service). The removed crystalline lens was cultured using a medium in which 30 mM galactose was added to M199 medium (manufactured by SIGMA).

An incubator was used for culturing each crystalline lens, and the temperature in the incubator was maintained at 37 ° C. Two days after the start of the culture, each crystalline lens was taken out from the medium and observed under a microscope using SZX12 (manufactured by Olympas). As a result, the cortex became cloudy.

Then, the crystalline lens cultured in the medium in which 30 mM galactose was added to the M199 medium was prepared by adding 30 mM galactose and a medium containing 10, 20 or 40 μM of an ATM inhibitor (specifically, AZD0156) to the M199 medium. Cultured using. Four days after the start of the first culture (two days after the start of the culture in the medium to which the inhibitor was added), each lens was taken out from the medium and observed under a microscope using SZX12 (manufactured by Olympas).

FIG. 6 shows the test results of microscopic observation. As is clear from FIG. 6, in the crystalline lens 2 days after the start of the first culture before the addition of the inhibitor, cloudiness of the cortex was observed, but 4 days after the start of the first culture after the addition of the ATM inhibitor. In the crystalline lens of the cortex, disappearance and dilution of the white turbidity of the cortex were confirmed. This indicates that the agent of the present invention has not only a preventive effect on cataract but also a therapeutic effect on cataract.

The present invention can be used as a prophylactic or therapeutic agent for cataract.

Claims (4)

It contains as an active ingredient an inhibitor that inhibits a signal transduction pathway that responds to DNA damage.
The inhibitor is 5- (5,6-dimethoxy-1H-benzimidazole-1-yl) -3- {[2- (trifluoromethyl) -benzyl] oxy} thiophene-2-carboxamide, 2,2-diphenyl-n. -(2,2,2-trichloro-1- [3- (4-fluoro-3-nitrophenyl) thioureide] ethyl) acetamide, 3-Amino-6- (4- (methylsulfonyl) phenyl)-N-phenylpyrazine-2 -carboxamide, 3-Amino-6- [4- (methylsulfonyl) phenyl]-N-phenyl-2-pyrazinecarboxamide, 2- (4-Morpholinyl) -6- (1-thianthrenyl) -4H-Pyran-4-one, 2- (Morpholin-4-yl) -6- (thianthren-1-yl) -4H-pyran-4-one, 8- [6- [3- (dimethylamino) propoxy] -3-pyridyl] -3-methyl -1-tetrahydropyran-4-yl-imidazo [4,5-c] quinolin-2-one, or a derivative or salt thereof, a prophylactic or therapeutic agent for cataract. The preventive or therapeutic agent for cataract according to claim 1 , which is an eye drop. The preventive or therapeutic agent for cataract according to claim 1 or 2 , wherein the cataract is diabetic cataract. 5- (5,6-dimethoxy-1H-benzimidazole-1-yl) -3- {[2- (trifluoromethyl) -benzyl] oxy} thiophene-2-carboxamide for producing prophylactic or therapeutic agents for cataracts , 2,2-diphenyl-n- (2,2,2-trichloro-1- [3- (4-fluoro-3-nitrophenyl) thioureide] ethyl) acetamide, 3-Amino-6- (4- (methylsulfonyl)) phenyl)-N-phenylpyrazine-2-carboxamide, 3-Amino-6- [4- (methylsulfonyl) phenyl]-N-phenyl-2-pyrazinecarboxamide, 2- (4-Morpholinyl) -6- (1-thianthrenyl)- 4H-Pyran-4-one, 2- (Morpholin-4-yl) -6- (thianthren-1-yl) -4H-pyran-4-one, 8- [6- [3- (dimethylamino) propoxy]- Use of 3-pyridyl] -3-methyl-1-tetrahydropyran-4-yl-imidazo [4,5-c] quinolin-2-one, or derivatives or salts thereof .

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