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Design, synthesis and biological evaluation of 4-fluoropyrrolidine-2-carbonitrile and octahydrocyclopenta[b]pyrrole-2-carbonitrile derivatives as dipeptidyl peptidase IV inhibitors

文献类型：期刊论文

作者Ji, Xun1,3; Xia, Chunmei1; Wang, Jiang1; Su, Mingbo1,2; Zhang, Lei1; Dong, Tiancheng1; Li, Zeng1; Wan, Xia1; Li, Jingya1; Li, Jia1
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2014-10-30
卷号86页码:242-256
关键词DPP4 inhibitors GLP-1 Selectivity Oral bioavailability Oral glucose tolerance tests hERG
ISSN号0223-5234
DOI10.1016/j.ejmech.2014.08.059
文献子类Article
英文摘要Based on the previous work in our group and the principle of computer-aided drug design, a series of novel beta-amino pyrrole-2-carbonitrile derivatives was designed and synthesized. Compounds 81 and 91 were efficacious and selective DPP4 inhibitors resulting in decreased blood glucose in vivo. Compound 81 had moderate DPP4 inhibitory activity (IC50 = 0.05 mu M) and good oral bioavailability (F = 53.2%). Compound 91 showed excellent DPP4 inhibitory activity (IC50 = 0.01 mu M), good selectivity (selective ratio: DPP8/DPP4 = 898.00; DPP9/DPP4 = 566.00) against related peptidases, and good efficacy in an oral glucose tolerance tests in ICR mice and moderate PR profiles (F = 22.8%, t(1/2) = 2.74 h). Moreover, compound 91 did not block hERG channel and exhibited no inhibition of liver metabolic enzymes such as CYP2C9. (C) 2014 Elsevier Masson SAS. All rights reserved.
WOS关键词METFORMIN-TREATED PATIENTS ; DPP-IV ; HIGHLY POTENT ; THERAPEUTIC PERSPECTIVES ; DISCOVERY ; INACTIVATION ; HYPERTENSION ; TELMISARTAN ; CHEMISTRY ; RAMIPRIL
资助项目National Natural Science Foundation of China[21021063] ; National Natural Science Foundation of China[91229204] ; National Natural Science Foundation of China[81125023] ; National Natural Science Foundation of China[81025017] ; National S&T Major Projects[2012ZX09103101-072] ; National S&T Major Projects[2012ZX09301001-005] ; National S&T Major Projects[2013ZX09507-001] ; Program of Shanghai Subject Chief Scientist[12XD1407100]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000343781800024
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/276863]  
专题国家新药筛选中心
药物发现与设计中心
药物化学研究室
药物安全性评价中心
通讯作者Li, Jia
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China;
2.E China Normal Univ, Shanghai 200062, Peoples R China
3.Shenyang Pharmaceut Univ, Sch Pharmaceut Engn, Shenyang 110016, Liaoning, Peoples R China;
推荐引用方式
GB/T 7714		 Ji, Xun,Xia, Chunmei,Wang, Jiang,et al. Design, synthesis and biological evaluation of 4-fluoropyrrolidine-2-carbonitrile and octahydrocyclopenta[b]pyrrole-2-carbonitrile derivatives as dipeptidyl peptidase IV inhibitors[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2014,86:242-256.
APA Ji, Xun.,Xia, Chunmei.,Wang, Jiang.,Su, Mingbo.,Zhang, Lei.,...&Liu, Hong.(2014).Design, synthesis and biological evaluation of 4-fluoropyrrolidine-2-carbonitrile and octahydrocyclopenta[b]pyrrole-2-carbonitrile derivatives as dipeptidyl peptidase IV inhibitors.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,86,242-256.
MLA Ji, Xun,et al."Design, synthesis and biological evaluation of 4-fluoropyrrolidine-2-carbonitrile and octahydrocyclopenta[b]pyrrole-2-carbonitrile derivatives as dipeptidyl peptidase IV inhibitors".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 86(2014):242-256.

入库方式： OAI收割

来源：上海药物研究所

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