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Design and Synthesis of 4-(2,4,5-Trifluorophenyl)butane-1,3-diamines as Dipeptidyl PeptidaseIV Inhibitors

文献类型：期刊论文

作者Zhu, Linrong2; Li, Yuanyuan1; Qiu, Ling3; Su, Mingbo1; Wang, Xin2; Xia, Chunmei1; Qu, Yi3; Li, Jingya1; Li, Jia1; Xiong, Bing2
刊名CHEMMEDCHEM
出版日期2013-07
卷号8期号:7页码:1104-1116
关键词1 3-diamines crystal structures dipeptidyl peptidaseIV inhibitors
ISSN号1860-7179
DOI10.1002/cmdc.201300104
文献子类Article
英文摘要The worldwide prevalence of diabetes has spurred numerous studies on the development of new antidiabetic medicines. As a result, dipeptidyl peptidaseIV (DPP4) has been recognized as a validated target. In our efforts to discover new DPP4 inhibitors, we analyzed the complexed structures of DPP4 available in Protein Data Bank and designed a series of triazole compounds. After enzyme activity assays and crystallographic verification of the binding interaction patterns, we found that the triazole compounds can inhibit DPP4 with micromolar IC50 values. Liver microsome stability and cytochrome P450 metabolic tests were performed on this series, revealing undesirable pharmacokinetic profiles for the triazole compounds. To overcome this liability, we substituted the triazole ring with an amide or urea group to produce a new series of DPP4 inhibitors. Based on its enzyme activity, metabolic stability, and selectivity over DPP8 and DPP9, we selected compound 21r for further study of its invivo effects in mice using an oral glucose tolerance test (OGTT). The results show that 21r has efficacy similar to that of sitagliptin at a dose of 3mgkg-1. The crystal structure of 21r bound to DPP4 also reveals that the trifluoromethyl group is directed toward a subpocket different from the subsite bound by sitagliptin, providing clues for the design of new DPP4 inhibitors.
WOS关键词GLUCAGON-LIKE PEPTIDE-1 ; IV INHIBITOR ; HIGHLY POTENT ; POLYPEPTIDE ; DEGRADATION ; DERIVATIVES ; EXPRESSION ; DISCOVERY ; RELEASE
资助项目Chinese Academy of Sciences[KSCX2-EW-Q-3-01] ; National Natural Science Foundation of China[30600784]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000320928400007
出版者WILEY-V C H VERLAG GMBH
源URL[http://119.78.100.183/handle/2S10ELR8/277563]  
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
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, State Key Lab Drug Res, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China;
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China;
3.Cent Hosp Xuhui Dist, Dept Geriatr, Shanghai 200031, Peoples R China
推荐引用方式
GB/T 7714		 Zhu, Linrong,Li, Yuanyuan,Qiu, Ling,et al. Design and Synthesis of 4-(2,4,5-Trifluorophenyl)butane-1,3-diamines as Dipeptidyl PeptidaseIV Inhibitors[J]. CHEMMEDCHEM,2013,8(7):1104-1116.
APA Zhu, Linrong.,Li, Yuanyuan.,Qiu, Ling.,Su, Mingbo.,Wang, Xin.,...&Shen, Jingkang.(2013).Design and Synthesis of 4-(2,4,5-Trifluorophenyl)butane-1,3-diamines as Dipeptidyl PeptidaseIV Inhibitors.CHEMMEDCHEM,8(7),1104-1116.
MLA Zhu, Linrong,et al."Design and Synthesis of 4-(2,4,5-Trifluorophenyl)butane-1,3-diamines as Dipeptidyl PeptidaseIV Inhibitors".CHEMMEDCHEM 8.7(2013):1104-1116.

入库方式： OAI收割

来源：上海药物研究所

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