Design, synthesis and biological evaluation of hetero-aromatic moieties substituted pyrrole-2-carbonitrile derivatives as dipeptidyl peptidase IV inhibitors

doi:10.1016/j.ejmech.2014.01.021

	Design, synthesis and biological evaluation of hetero-aromatic moieties substituted pyrrole-2-carbonitrile derivatives as dipeptidyl peptidase IV inhibitors
	Ji, Xun 2,3; Su, Mingbo 1,3; Wang, Jiang3 ; Deng, Guanghui 3; Deng, Sisi 3; Li, Zeng 3; Tang, Chunlan 3; Li, Jingya3 ; Li, Jia3 ; Zhao, Linxiang 2
刊名	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
	2014-03-21
卷号	75 页码:111-122
关键词	DPP4 inhibitors Selectivity Reversible kinetic characterization Oral bioavailability Oral glucose tolerance test
ISSN号	0223-5234
DOI	10.1016/j.ejmech.2014.01.021
文献子类	Article
英文摘要	A series of novel hetero-aromatic moieties substituted alpha-amino pyrrole-2-carbonitrile derivatives was designed and synthesized based on structure-activity relationships (SARs) of pyrrole-2-carbonitrile inhibitors. All compounds demonstrated good dipeptidyl peptidase IV (DPP4) inhibitory activities (IC50 = 0.004-113.6 mu M). Moreover, compounds 6h (IC50 = 0.004 mu M) and 6n (IC50 = 0.01 mu M) showed excellent inhibitory activities against DPP4, good selectivity (compound 6h, selective ratio: DPP8/DPP4 = 450.0; DPP9/DPP4 = 375.0; compound 6n, selective ratio: DPP8/DPP4 = 470.0; DPP9/DPP4 = 750.0) and good efficacy in an oral glucose tolerance test in ICR mice. Furthermore, compounds 6h and 6n demonstrated moderate PK properties (compound 6h, F% = 37.8%, t(1/2) = 1.45 h; compound 6n, F% = 16.8%, t(1/2) = 3.64 h). (C) 2014 Elsevier Masson SAS. All rights reserved.
资助项目	National Natural Science Foundation of China[21021063] ; National Natural Science Foundation of China[91229204] ; National Natural Science Foundation of China[81025017] ; National Natural Science Foundation of China[81125023] ; 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关键词	METFORMIN-TREATED PATIENTS ; BORONIC ACID INHIBITORS ; DPP-IV ; HIGHLY POTENT ; ANTIHYPERGLYCEMIC PROPERTIES ; IN-VIVO ; DISCOVERY ; SERIES ; INACTIVATION ; EFFICACY
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS记录号	WOS:000333775600012
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/277152]
专题	药物化学研究室
通讯作者	Liu, Hong
作者单位	1.E China Normal Univ, Shanghai 200062, Peoples R China 2.Shenyang Pharmaceut Univ, Sch Pharmaceut Engn, Shenyang 110016, Liaoning, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China;
推荐引用方式 GB/T 7714	Ji, Xun,Su, Mingbo,Wang, Jiang,et al. Design, synthesis and biological evaluation of hetero-aromatic moieties substituted pyrrole-2-carbonitrile derivatives as dipeptidyl peptidase IV inhibitors[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2014,75:111-122.
APA	Ji, Xun.,Su, Mingbo.,Wang, Jiang.,Deng, Guanghui.,Deng, Sisi.,...&Liu, Hong.(2014).Design, synthesis and biological evaluation of hetero-aromatic moieties substituted pyrrole-2-carbonitrile derivatives as dipeptidyl peptidase IV inhibitors.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,75,111-122.
MLA	Ji, Xun,et al."Design, synthesis and biological evaluation of hetero-aromatic moieties substituted pyrrole-2-carbonitrile derivatives as dipeptidyl peptidase IV inhibitors".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 75(2014):111-122.