CN116410298B - 一种三激动多肽化合物及其盐、药用组合物、药剂和用途 - Google Patents
一种三激动多肽化合物及其盐、药用组合物、药剂和用途 Download PDFInfo
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Abstract
本发明公开了一种三激动多肽化合物及其盐、药用组合物、药剂和用途，属于多肽药物化学技术领域。该GLP‑1、GIP和GCG三激动多肽化合物的氨基酸序列为：BGS‑3：HAibHGTFTSDYSIAibLEKIAQKAFVQWLLEGGPSSGAPPPS‑NH2。本发明还公开了该GLP‑1、GIP和GCG三激动多肽化合物药学上可接受的盐、药物组合物和药剂。本发明多肽化合物同时具备减重效果，可以作为有效原料用于制备减肥药物。
Description
技术领域
本发明涉及多肽化合物技术领域，具体涉及一种三激动多肽化合物及其盐、药用组合物、药剂和用途。
背景技术
全球范围内获批上市了多种作用机制的多个减肥药物，国内目前唯一获批的用于肥胖或体重超重(BMI≥24kg/m2)患者的治疗药物仅有奥利司他胶囊，其主要通过减少食物中脂肪吸收来降低体重，但其减重效果一般，并可导致脂肪泻、胃肠不适，维生素缺乏等药物不良反应，其在临床上的应用并不广泛。在国内的减肥药物存在远未被满足的临床需求。
目前国外已上市GLP-1受体单激动剂减肥药，如利拉鲁肽和司美格鲁肽，其中司美格鲁肽68周治疗的患者体重减轻了12.4%，并且69%的患者体重减轻超过10%，同时2022年其全球市场销售额超100亿美金，礼来首个GLP-1R/GIPR双靶点药物替尔泊肽上市且实现疗效升级，诺和诺德下一代产品CagriSema早期数据亮眼并推向3期临床，礼来的首个GLP-1R/GIPR/GCGR三激动剂3期临床数据惊艳，但国内的减肥市场需要更为安全有效的减肥药物，目前国内仍然无临床研究的GLP-1R/GIPR/GCGR三激动剂。GLP-1R、GIPR和GCGR受体下游信号传导错综复杂，对糖脂代谢均可能存在正负反馈调节，也增加了设计一条理想的多重活性杂合肽的难度。本领域将设计一类具有GLP-1R/GIPR/GCGR三激动生物活性强、半衰期长和免疫原性低的杂合多肽。
发明内容
本发明的目的在于克服现有技术的不足，提出一种三激动多肽化合物及其盐、药用组合物、药剂和用途，将设计一类具有GLP-1R/GIPR/GCGR三激动生物活性强、半衰期长和免疫原性低的杂合多肽。
本发明的目的是通过以下技术方案来实现的：
GLP-1、GIP和GCG三激动多肽化合物，该多肽化合物的氨基酸序列为：
BGS-3：
HAibHGTFTSDYSIAibLEKIAQKAFVQWLLEGGPSSGAPPPS-NH2；
其中所有的Aib均为2-氨基异丁酸；
其中BGS-3第20位字母K为脂肪酸链接位置，其中侧链被修饰的K为 K(AEEA-AEEA-γ-Glu-CO-(CH2)n-COOH)；
其中，n为自然数，且12≤n≤20。
进一步的，所述n是14、16、18或20。
本发明还提供一类GLP-1、GIP和GCG三激动多肽化合物的药学上可接受的盐。药学上可接受的盐和制备它们的常用方法是本领域公知的。
进一步的，一类GLP-1、GIP和GCG三激动多肽化合物的药学上可接受的盐由多肽化合物与无机酸、有机酸中的任意一种反应形成。
进一步的，所述的盐为GLP-1、GIP和GCG三激动多肽化合物与下述化合物中的一种所形成的盐：盐酸、马来酸、甲磺酸、磷酸、乙磺酸、甲酸、对甲苯磺酸、乙酸、乙酰乙酸、丙酮酸、果胶酯酸、丁酸、己酸、苯磺酸、庚酸、十一烷酸、苯甲酸、氢溴酸、水杨酸、月桂酸、2-(4-羟基苯甲酰基)苯甲酸、肉桂酸、樟脑酸、环戊烷丙酸、3-羟基-2-萘甲酸、樟脑磺酸、二葡糖酸、烟酸、扑酸、丙酸、过硫酸、苦味酸、3-苯基丙酸、特戊酸、衣康酸、2-羟基乙磺酸、氨基磺酸、十二烷基硫酸、三氟甲磺酸、萘二磺酸、2-萘磺酸、柠檬酸、扁桃酸、抗坏血酸、酒硬脂酸、石酸、草酸、乳酸、琥珀酸、丙二酸、半硫酸、苹果酸、藻酸、富马酸、D-葡糖酸、甘油磷酸、天冬氨酸、硫氰酸或者磺基水杨酸。
本发明还提供了GLP-1、GIP和GCG三激动多肽化合物的药用组合物，该药用组合物以GLP-1、GIP和GCG三激动多肽化合物为有效原料，或者以GLP-1、GIP和GCG三激动多肽化合物药学上可接受的盐为有效原料，还包括药学上可接受的载体、稀释剂或赋形剂。
进一步的，所述药学上可接受的载体包括粘合剂、润滑剂、崩解剂、增溶剂、分散剂、稳定剂、悬浮剂、着色剂、调味剂、缓冲剂、增溶剂、等渗剂中的一种或多种。
本发明还提供了含有上述GLP-1、GIP和GCG三激动多肽化合物所制备的药剂，所述的药剂是任何一种药剂学上所说的片剂、胶囊、酏剂、糖浆、锭剂、吸入剂、喷雾剂、注射剂、膜剂、贴剂、散剂、颗粒剂、块剂、乳剂、栓剂或者复方制剂。
本发明还提供了含有上述的GLP-1、GIP和GCG三激动多肽化合物的用途，所述的用途为GLP-1、GIP和GCG三激动多肽化合物作为有效原料用于制备治疗或者预防肥胖症药物中的用途，或者用于制备治疗或者预防脂肪肝病药物中的用途，或者用于制备治疗或预防非酒精性脂肪性肝疾病药物中的用途，或者用于制备治疗或预防血脂异常药物中的用途，或者用于制备治疗或预防代谢综合症药物中的用途。
本发明提供了含有上述GLP-1、GIP和GCG三激动多肽化合物药学上可接受的盐的用途，所述的用途为多肽化合物药学上可接受的盐作为有效原料在用于制备治疗或者预防肥胖症药物中的用途，或者用于制备治疗或者预防脂肪肝病药物中的用途，或者用于制备治疗或预防非酒精性脂肪性肝疾病药物中的用途，或者用于制备治疗或预防血脂异常药物中的用途，或者用于制备治疗或预防代谢综合症药物中的用途。
在本说明书全文中，采用以下缩写的含义见下表：
本发明的有益效果是：
（1）本发明的GLP-1、GIP和GCG三激动多肽化合物对GLP-1受体和GIP受体的激动活性高于各受体的天然配体，同时对GCG受体具有更低的激动活性。
本发明提供的GLP-1、GIP和GCG三激动多肽化合物引入非天然氨基酸和脂肪链修饰，化学性质稳定，不易被体内的DPP-IV和NEP降解，不易被肾小球滤过，化合物的稳定性显著提高，具有支持每周一次给药的药代动力学特征。
（3）与现有的GLP-1受体激动剂相比，本发明的GLP-1、GIP和GCG三激动多肽化合物在更为有效促进减重和防止增重作用，逆转胰岛素抵抗，调节脂质代谢，与现有药物相比具有意想不到的有益作用。
附图说明
图1为不同组别小鼠体重变化结果图；
图2为不同组别小鼠体重变化率结果图；
图3为终点时各组小鼠体重结果图；
图4为不同组别小鼠的每天摄食量变化结果图；
图5为不同组别小鼠累积摄食量变化结果图；
图6为不同组别小鼠OGTT试验结果第一结果图；
图7为不同组别小鼠OGTT试验结果第二结果图；
图8为终点时不同组别小鼠肝脏/脂肪体重比结果图；
图9为终点时不同组别小鼠血生化检测结果图。
具体实施方式
下面将结合实施例，对本发明的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域技术人员在没有付出创造性劳动的前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例1（关于GLP-1、GIP和GCG三激动多肽化合物对GLP-1受体、GCG受体和GIP受体的激动活性测定）
GLP-1、GIP和GCG三激动多肽化合物样品的氨基酸序列为：
BGS-3：
HAibHGTFTSDYSIAibLEKIAQKAFVQWLLEGGPSSGAPPPS-NH2；
其中所有的Aib均为2-氨基异丁酸；
其中BGS-3的第20位字母K为脂肪酸链接位置，其中侧链被修饰的K为 K(AEEA-AEEA-γ-Glu-CO-(CH2)n-COOH)；
其中，n为16。
通过受体功能测定法来确定多肽化合物对受体的激动作用，所述测定法CHO细胞稳定表达GLP-1受体、GCG受体或GIP受体和含cAMP反应元件的Luciferase报告基因，多肽药物刺激稳定细胞后能够通过cAMP/PKA信号通路促进报告基因Luciferase的表达，通过检测Luciferase催化底物产生的荧光来检测刺激药物的活性。
将稳定表达上述三种受体的细胞分入T75培养瓶并在培养基(DMEM/10％FBS)中过夜生长至接近汇合状态，然后除去培养基，并用PBS洗涤细胞，加入0.05％Trypsin消化液消化3分钟，然后加入DMEM基础培养基终止消化，离心收集细胞。用DMEM空白培养基调整细胞密度为1×105个/ml，100μl/孔接种于96孔细胞培养板中，于37℃、5％二氧化碳条件下培养过夜。
药物处理：将多肽样品用稀释液预稀释至5μg/ml，作为第一个稀释浓度，然后在96孔板中用稀释液按3倍比依次稀释8次，共9个浓度；稀释后各浓度样品加入细胞板中，每孔加100 μl，平行做双复孔，稀释液作为空白对照，于37℃、5% 二氧化碳培养箱约5 h。
检测和结果分析：将荧光素酶检测试剂盒平衡至室温，将每孔100μl荧光素酶试剂加入细胞板中，200 rpm室温振荡避光反应10 min，多功能酶标仪测定化学发光RLU值。以化学发光单位值（RLU）为纵坐标，以样品浓度为横坐标，使用酶标仪自带软件进行四参数逻辑拟合计算EC50。
表1.多肽对GLP-1、GCG和GIP受体激动活性测定
结果如表1所示，BGS-3对三种受体均具有较强的激动活性，尤其是对GLP-1受体的激动活性最强。
实施例2（关于GLP-1、GIP和GCG三激动多肽化合物对血清的稳定性测定）
GLP-1、GIP和GCG三激动多肽化合物样品的氨基酸序列为：
BGS-3：
HAibHGTFTSDYSIAibLEKIAQKAFVQWLLEGGPSSGAPPPS-NH2；
其中所有的Aib均为2-氨基异丁酸；
其中BGS-3的第20位字母K为脂肪酸链接位置，其中侧链被修饰的K为 K(AEEA-AEEA-γ-Glu-CO-(CH2)n-COOH)；
其中，n为18。
受试样品于37℃与人血清共孵0，24，48，72小时，使用实施例1的活性测定方法检测多肽化合物的血清稳定性。
表2.多肽血清稳定性生物活性检测数据
该时刻相对百分比数是由对应受体0h时EC50的数据除以该时刻对应受体EC50的数据得到，例如BGS-3-24h在GLP-1受体的相对百分比数为 151.0/104.5=144.5%。
如表2所示，以BGS-3的0时样品生物活性为100%，BGS-3在各个时间点对三种受体的激动活性均未受影响，表明其在血清中非常稳定。
实施例3（关于GLP-1、GIP和GCG三激动多肽化合物对饮食诱导肥胖(DIO)小鼠体重的影响）
GLP-1、GIP和GCG三激动多肽化合物样品的氨基酸序列为：
BGS-3：
HAibHGTFTSDYSIAibLEKIAQKAFVQWLLEGGPSSGAPPPS-NH2；
其中所有的Aib均为2-氨基异丁酸；
其中BGS-3的第20位字母K为脂肪酸链接位置，其中侧链被修饰的K为 K(AEEA-AEEA-γ-Glu-CO-(CH2)n-COOH)；
其中，n为20。
雄性C57BL/6J小鼠，体重22g左右，模型组共30只，用高脂饲料饲养18周制造DIO小鼠模型。空白对照组6只采用标准鼠饲料饲养(对照标准饮食组)，为G1组。在给药开始前，各组DIO小鼠按照体重随机分组，共分为4组，每组6只，分别为G2、G3、G4、G5组。
试验后G1组使用标准鼠饲料饲养，给药药物为PBS缓冲液；G2组使用高脂饲料进行喂养，给药药物为PBS缓冲液；G3组使用高脂饲料进行喂养，给药药物由索马鲁肽制成的供给品1溶液；G4组使用高脂饲料进行喂养，给药药物由替尔泊肽制成的供给品2溶液；G5组使用高脂饲料进行喂养，给药药物由实施例3肽化合物制成的供给品3溶液。
各组按照试验设计于D0开始给药。给药日期为：D0、D3、D7、D10、D14、D17、D21和D24。
给药体积：根据小鼠体重调整，小鼠给药体积= 5 μL/g ×小鼠体重（g）。
数据采集：
（1）药效期小鼠每天称重；
（2）每天各组小鼠检测摄食量，计算平均每日摄食量和累积摄食量；
（3）首次给药后24h，进行OGTT检测（葡萄糖剂量：2 g/kg，0，15，30，60，120min）；
（4）末次给药后进行一次体脂比检测。
样品收集：D28试验终点，试验终点处理如下：
（1）取肝脏组织称重，之后液氮速冻，-80℃暂时保存，计算肝重体重比，肝脏样品待委托方确认数据后进行处理，无需保存；
（2）收集小鼠脂肪组织：①腹股沟脂肪、②附睾脂肪、③肾周脂肪、④肠系膜脂肪、⑤肩胛骨下棕色脂肪，五部分分别进行称重记录，计算各部分脂肪体重比，再计算白色脂肪（①-④加和）体重比。
参考图1-图9，研究结果显示：与模型对照组G2（PBS）相比，G5组（BGS-3组）,给药后均可显著降低小鼠体重、OGTT，显著降低腹股沟皮下脂肪体重比、肠系膜脂肪体重比和肩胛骨棕色脂肪体重比，显著降低血浆CHOL和LDL-C水平。各BGS-3组对小鼠摄食有抑制作用，对ALT、AST有改善作用。
以上所述仅是本发明的优选实施方式，应当理解本发明并非局限于本文所披露的形式，不应看作是对其他实施例的排除，而可用于各种其他组合、修改和环境，并能够在本文所述构想范围内，通过上述教导或相关领域的技术或知识进行改动。而本领域人员所进行的改动和变化不脱离本发明的精神和范围，则都应在本发明所附权利要求的保护范围内。
Claims (10)
1.GLP-1、GIP和GCG三激动多肽化合物，其特征在于，该多肽化合物的名称为BGS-3，该多肽化合物的氨基酸序列为：
HAibHGTFTSDYSIAibLEKIAQKAFVQWLLEGGPSSGAPPPS-NH2；
其中所有的Aib均为2-氨基异丁酸；
其中BGS-3的第20位字母K为脂肪酸链接位置，其中侧链被修饰的K为 K(AEEA-AEEA-γ-Glu-CO-(CH2)n-COOH)；
其中，n为自然数，且12≤n≤20。
2.根据权利要求1所述的GLP-1、GIP和GCG三激动多肽化合物，其特征在于：所述n是14、16、18或20。
3.权利要求1中所述的GLP-1、GIP和GCG三激动多肽化合物药学上可接受的盐。
4.根据权利要求3所述的GLP-1、GIP和GCG三激动多肽化合物药学上可接受的盐，其特征在于：由权利要求1或2所述的GLP-1、GIP和GCG三激动多肽化合物与无机酸、有机酸中的任意一种反应形成。
5.根据权利要求4所述的GLP-1、GIP和GCG三激动多肽化合物药学上可接受的盐，其特征在于：所述的盐为GLP-1、GIP和GCG三激动多肽化合物与下述化合物中的一种所形成的盐：盐酸、马来酸、甲磺酸、磷酸、乙磺酸、甲酸、对甲苯磺酸、乙酸、乙酰乙酸、丙酮酸、果胶酯酸、丁酸、己酸、苯磺酸、庚酸、十一烷酸、苯甲酸、氢溴酸、水杨酸、月桂酸、2-(4-羟基苯甲酰基)苯甲酸、肉桂酸、樟脑酸、环戊烷丙酸、3-羟基-2-萘甲酸、樟脑磺酸、二葡糖酸、烟酸、扑酸、丙酸、过硫酸、苦味酸、3-苯基丙酸、特戊酸、衣康酸、2-羟基乙磺酸、氨基磺酸、十二烷基硫酸、三氟甲磺酸、萘二磺酸、2-萘磺酸、柠檬酸、扁桃酸、抗坏血酸、酒硬脂酸、石酸、草酸、乳酸、琥珀酸、丙二酸、半硫酸、苹果酸、藻酸、富马酸、D-葡糖酸、甘油磷酸、天冬氨酸、硫氰酸或者磺基水杨酸。
6.GLP-1、GIP和GCG三激动多肽化合物的药用组合物，其特征在于，该药用组合物以权利要求1或2所述的GLP-1、GIP和GCG三激动多肽化合物为有效原料，或者以权利要求3-5中任一所述的GLP-1、GIP和GCG三激动多肽化合物药学上可接受的盐为有效原料，还包括药学上可接受的载体、稀释剂或赋形剂。
7.根据权利要求6所述的GLP-1、GIP和GCG三激动多肽化合物的药用组合物，其特征在于：所述药学上可接受的载体包括粘合剂、润滑剂、崩解剂、分散剂、稳定剂、悬浮剂、着色剂、调味剂、缓冲剂、增溶剂、等渗剂中的一种或多种。
8.权利要求1或2中任意一项所述的GLP-1、GIP和GCG三激动多肽化合物所制备的药剂，其特征在于，所述的药剂为片剂、胶囊、酏剂、糖浆、锭剂、吸入剂、喷雾剂、注射剂、膜剂、贴剂、散剂、颗粒剂、块剂、乳剂、栓剂或者复方制剂。
9.权利要求1或2中任意一项所述的GLP-1、GIP和GCG三激动多肽化合物的用途，其特征在于，所述的用途为GLP-1、GIP和GCG三激动多肽化合物作为有效原料用于制备治疗肥胖症药物中的用途，或者用于制备治疗脂肪肝病药物中的用途，或者用于制备治疗血脂异常药物中的用途，或者用于制备治疗代谢综合症药物中的用途。
10.权利要求3-5项中任意一项所述的GLP-1、GIP和GCG三激动多肽化合物药学上可接受的盐的用途，其特征在于，所述的用途为GLP-1、GIP和GCG三激动多肽化合物药学上可接受的盐作为有效原料在用于制备治疗肥胖症药物中的用途，或者用于制备治疗脂肪肝病药物中的用途，或者用于制备治疗血脂异常药物中的用途，或者用于制备治疗代谢综合症药物中的用途。
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