Design, synthesis and structure activity relationship studies of GPR40 agonists containing amide linker
文献类型：期刊论文
| 作者 | Chen, Tingting1,2; Ning, Mengmeng1 ; Ye, Yangliang1; Wang, Kai1; Leng, Ying1; Shen, Jianhua1
|
| 刊名 | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2018-05-25 |
| 卷号 | 152页码:175-194 |
| 关键词 | GPR40 FFAR1 Insulin secretion Type 2 diabetes mellitus CNS |
| ISSN号 | 0223-5234 |
| DOI | 10.1016/j.ejmech.2018.04.023 |
| 文献子类 | Article |
| 英文摘要 | Free fatty acid receptor 1 (FFAR1/GPR40) attracted significant attention as a potential target for developing novel antidiabetic drugs because of its unique mechanism in glucose homeostasis. Several reports have expressed concerns about central nervous system (CNS) penetration of GPR40 agonists, which is possibly attributed to their high lipophilicity and low total polar surface area. Herein, we report our efforts to improve the physicochemical properties and pharmacokinetic profiles of LY2881835, a GPR40 agonist that had undergone Phase I clinical trial, through a series of structural optimizations. We identified an orally efficacious compound, 15k, which possessed increased plasma exposure, prolonged half-life and reduced CNS exposure and liver to plasma distribution ratio compared with LY2881835. 15k is a potentially valuable lead compound in the development of safe and efficacious GPR40-targeted drugs to treat type 2 diabetes mellitus. (C) 2018 Elsevier Masson SAS. All rights reserved. |
| WOS关键词 | TYPE-2 DIABETES-MELLITUS ; FATTY-ACID RECEPTOR ; PANCREATIC BETA-CELLS ; INSULIN-SECRETION ; IN-VIVO ; DISCOVERY ; POTENT ; SULFONYLUREAS ; INVOLVEMENT ; FASIGLIFAM |
| 资助项目 | National Natural Science Foundation of China[81473093] ; State Key laboratory of Drug Research, Shanghai Institute of Materia Medica[SIMM160122-02] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000435048900015 |
| 出版者 | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/279742]  |
| 专题 | 药理学第一研究室 中科院受体结构与功能重点实验室 新药研究国家重点实验室 药物发现与设计中心 |
| 通讯作者 | Leng, Ying; Shen, Jianhua |
| 作者单位 | 1.Chinese Acad Sci, SIMM, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China; 2.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China |
| 推荐引用方式 GB/T 7714 | Chen, Tingting,Ning, Mengmeng,Ye, Yangliang,et al. Design, synthesis and structure activity relationship studies of GPR40 agonists containing amide linker[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2018,152:175-194. |
| APA | Chen, Tingting,Ning, Mengmeng,Ye, Yangliang,Wang, Kai,Leng, Ying,&Shen, Jianhua.(2018).Design, synthesis and structure activity relationship studies of GPR40 agonists containing amide linker.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,152,175-194. |
| MLA | Chen, Tingting,et al."Design, synthesis and structure activity relationship studies of GPR40 agonists containing amide linker".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 152(2018):175-194. |
入库方式： OAI收割
来源：上海药物研究所
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