A novel approach to exploit Small-Molecule glucagon-like Peptide-1 receptor agonists with high potency
文献类型：期刊论文
| 作者 | Wang, Xiaoyan3,4; Yun, Ying2; Chen, Lili3,4 ; Guo, Shimeng4; Niu, Buying3,4; Fang, Jiahui4; Yuan, Qianting4; Shen, Jianhua3,4; Xie, Xin1,2,4; Wang, Kai4
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| 刊名 | BIOORGANIC & MEDICINAL CHEMISTRY
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| 出版日期 | 2024-06-01 |
| 卷号 | 107页码:19 |
| 关键词 | Diabetes GLP-1 receptor Agonist Structural optimization Water molecule replacement Structure activity relationship Docking simulation |
| ISSN号 | 0968-0896 |
| DOI | 10.1016/j.bmc.2024.117761 |
| 通讯作者 | Xie, Xin(xxie@simm.ac.cn) ; Wang, Kai(kwang@simm.ac.cn) |
| 英文摘要 | Small-molecule glucagon-like peptide-1 receptor (GLP-1R) agonists are recognized as promising therapeutics for type 2 diabetes mellitus (T2DM) and obesity. Danuglipron, an investigational small-molecule agonist, has demonstrated high efficacy in clinical trials. However, further development of danuglipron is challenged by a high rate of gastrointestinal adverse events. While these effects may be target-related, it is plausible that the carboxylic acid group present in danuglipron may also play a role in these outcomes by affecting the pharmacokinetic properties and dosing regimen of danuglipron, as well as by exerting direct gastrointestinal irritation. Therefore, this study aims to replace the problematic carboxylic acid group by exploring the internal binding cavity of danuglipron bound to GLP-1R using a water molecule displacement strategy. A series of novel triazolecontaining compounds have been designed and synthesized during the structure-activity relationship (SAR) study. These efforts resulted in the discovery of compound 2j with high potency (EC50 = 0.065 nM). Moreover, docking simulations revealed that compound 2j directly interacts with the residue Glu387 within the internal cavity of GLP-1R, effectively displacing the structural water previously bound to Glu387. Subsequent in vitro and in vivo experiments demonstrated that compound 2j had comparable efficacy to danuglipron in enhancing insulin secretion and improving glycemic control. Collectively, this study offers a practicable approach for the discovery of novel small-molecule GLP-1R agonists based on danuglipron, and compound 2j may serve as a lead compound to further exploit the unoccupied internal cavity of danuglipron's binding pocket. |
| WOS关键词 | ACTIVATION ; PRODRUGS |
| 资助项目 | National Natural Science Foundation of China[SIMM0320231004] ; [82273764] ; [82121005] ; [82330113] ; [82304579] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:001245323600001 |
| 出版者 | PERGAMON-ELSEVIER SCIENCE LTD |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/311395]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Xie, Xin; Wang, Kai |
| 作者单位 | 1.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Peoples R China 2.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China 3.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Mat Med SIMM, State Key Lab Drug Res, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Wang, Xiaoyan,Yun, Ying,Chen, Lili,et al. A novel approach to exploit Small-Molecule glucagon-like Peptide-1 receptor agonists with high potency[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2024,107:19. |
| APA | Wang, Xiaoyan.,Yun, Ying.,Chen, Lili.,Guo, Shimeng.,Niu, Buying.,...&Wang, Kai.(2024).A novel approach to exploit Small-Molecule glucagon-like Peptide-1 receptor agonists with high potency.BIOORGANIC & MEDICINAL CHEMISTRY,107,19. |
| MLA | Wang, Xiaoyan,et al."A novel approach to exploit Small-Molecule glucagon-like Peptide-1 receptor agonists with high potency".BIOORGANIC & MEDICINAL CHEMISTRY 107(2024):19. |
入库方式： OAI收割
来源：上海药物研究所
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