Discovery of orally effective and safe GPR40 agonists by incorporating a chiral, rigid and polar sulfoxide into 8-position to the carboxylic acid
文献类型：期刊论文
| 作者 | Chen, Cheng3,4,5; Guo, Shi-Meng3; Sun, Yuanjun5; Li, He3; Hu, Nan2; Yao, Kun5; Ni, Huxin5; Xia, Zhikan1,3; Xu, Bin4; Xie, Xin3
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| 刊名 | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2023-05-05 |
| 卷号 | 251页码:115267 |
| 关键词 | GPR40 Glucose-stimulated insulin secretion Type 2 diabetes mellitus Lipophilicity Liver safety Three-in-one pharmacophore 2-(phenylsulfinyl)acetic acid |
| DOI | 10.1016/j.ejmech.2023.115267 |
| 文献子类 | Article |
| 英文摘要 | GPR40 is primarily expressed in pancreatic islet 8 -cells, and its activation by endogenous ligands of medium to long-chain free fatty acids or synthetic agonists is clinically proved to improve glycemic control by stimulating glucose-dependent insulin secretion. However, most of the reported agonists are highly lipophilic, which might cause lipotoxicity and the off-target effects in CNS. Particularly, the withdrawal of TAK-875 from clinical trials phase III due to liver toxicity concern threw doubt over the long-term safety of targeting GPR40. Improving the efficacy and the selectivity, thus enlarging the therapeutic window would provide an alternative to develop safe GPR40-targeted therapeutics. Herein, by employing an innovative three-in-one pharmacophore drug design strategy, the optimal structural features for GPR40 agonist was integrated into one functional group of sulfoxide, which was incorporated into the 8 -position of the propanoic acid core pharmacophore. As a result, the confor-mational constraint, polarity as well as chirality endowed by the sulfoxide significantly enhanced the efficacy, selectivity and ADMET properties of the novel (S)-2-(phenylsulfinyl)acetic acid-based GPR40 agonists. The lead compounds (S)-4a and (S)-4s exhibited robust plasma glucose-lowering effects and insulinotropic action during an oral glucose tolerance test in C57/BL6 mice, excellent pharmacokinetic profile and little hepatobiliary transporter inhibition, marginal cell toxicities against human primary hepatocyte at 100 mu M. |
| WOS关键词 | PROTEIN-COUPLED RECEPTORS ; FASIGLIFAM TAK-875 ; DRUG DISCOVERY ; FULL AGONISTS ; IN-VITRO ; POTENT ; OPTIMIZATION ; EFFICACY ; LIPOPHILICITY ; TARGETS |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000954767500001 |
| 出版者 | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/309670]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Xie, Xin; Long, Ya-Qiu |
| 作者单位 | 1.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China 2.Soochow Univ, Dept Pharm, Affiliated Hosp 3, 185 Juqian St, Changzhou 213003, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 4.Shanghai Univ, Dept Chem, 99 Shangda Rd, Shanghai 200444, Peoples R China; 5.Soochow Univ, Coll Pharmaceut Sci, 199 Renai Rd, Suzhou 215123, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Chen, Cheng,Guo, Shi-Meng,Sun, Yuanjun,et al. Discovery of orally effective and safe GPR40 agonists by incorporating a chiral, rigid and polar sulfoxide into 8-position to the carboxylic acid[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2023,251:115267. |
| APA | Chen, Cheng.,Guo, Shi-Meng.,Sun, Yuanjun.,Li, He.,Hu, Nan.,...&Long, Ya-Qiu.(2023).Discovery of orally effective and safe GPR40 agonists by incorporating a chiral, rigid and polar sulfoxide into 8-position to the carboxylic acid.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,251,115267. |
| MLA | Chen, Cheng,et al."Discovery of orally effective and safe GPR40 agonists by incorporating a chiral, rigid and polar sulfoxide into 8-position to the carboxylic acid".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 251(2023):115267. |
入库方式： OAI收割
来源：上海药物研究所
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