Design and optimization of 2,3-dihydrobenzo[b][1,4]dioxine propanoic acids as novel GPR40 agonists with improved pharmacokinetic and safety profiles
文献类型：期刊论文
| 作者 | Guo, Bin3 ; Guo, Shimeng1; Huang, Jing2; Li, Jingya1; Li, Jia1; Chen, Qian3; Zhou, Xianli2; Xie, Xin1; Yang, Yushe3
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| 刊名 | BIOORGANIC & MEDICINAL CHEMISTRY
 |
| 出版日期 | 2018-12-01 |
| 卷号 | 26期号:22页码:5780-5791 |
| 关键词 | GPR40 agonist 2,3-Dihydrobenzo[b][1,4]dioxine Insulin secretion Type 2 diabetes mellitus |
| ISSN号 | 0968-0896 |
| DOI | 10.1016/j.bmc.2018.10.019 |
| 文献子类 | Article |
| 英文摘要 | GPR40 has become a new potential therapeutic target for the treatment of diabetes due to its role in mediating the enhancement of glucose-stimulated insulin secretion in pancreatic beta cells with a low risk of hypoglycemia. As an effort to extend the chemical space and identify structurally distinct GPR40 agonists with improved liver safety, a novel series of fused-ring phenyl propanoic acid analogues were designed. Comprehensive structure-activity relationship studies around novel scaffolds were conducted and led to several analogues exhibited potent GPR40 agonistic activities and high selectivity against other fatty acid receptors. Further evaluation of pharmacokinetic (PK) profiles and in vivo efficacy identified compound 40a with excellent PK properties and significant glucose-lowering efficacy during an oral glucose tolerance test. In addition, compound 40a displayed lower hepatobiliary transporter inhibition and favorable druggability. All results indicate that compound 40a is a promising candidate for further development. |
| WOS关键词 | RECEPTOR 1 AGONIST ; 3-ARYL-3-ETHOXYPROPANOIC ACIDS ; DISCOVERY ; POTENT ; DRUGS ; IDENTIFICATION ; TAK-875 |
| 资助项目 | National Natural Science Foundation of China[21402222] ; "Personalized Medicines Molecular Signature-Based Drug Discovery and Development", Strategic Priority Research Program of Chinese Academy of Sciences[XDA12040307] ; Youth Innovation Promotion Association of Chinese Academy of Sciences[2016262] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:000451196900003 |
| 出版者 | PERGAMON-ELSEVIER SCIENCE LTD |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/279480]  |
| 专题 | 国家新药筛选中心 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 药物化学研究室 |
| 通讯作者 | Xie, Xin; Yang, Yushe |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China; 2.Southwest Jiao Tong Univ, Sch Life Sci & Engn, Chengdu 610031, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Guo, Bin,Guo, Shimeng,Huang, Jing,et al. Design and optimization of 2,3-dihydrobenzo[b][1,4]dioxine propanoic acids as novel GPR40 agonists with improved pharmacokinetic and safety profiles[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2018,26(22):5780-5791. |
| APA | Guo, Bin.,Guo, Shimeng.,Huang, Jing.,Li, Jingya.,Li, Jia.,...&Yang, Yushe.(2018).Design and optimization of 2,3-dihydrobenzo[b][1,4]dioxine propanoic acids as novel GPR40 agonists with improved pharmacokinetic and safety profiles.BIOORGANIC & MEDICINAL CHEMISTRY,26(22),5780-5791. |
| MLA | Guo, Bin,et al."Design and optimization of 2,3-dihydrobenzo[b][1,4]dioxine propanoic acids as novel GPR40 agonists with improved pharmacokinetic and safety profiles".BIOORGANIC & MEDICINAL CHEMISTRY 26.22(2018):5780-5791. |
入库方式： OAI收割
来源：上海药物研究所
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