Design, Synthesis, and Pharmacological Evaluation of Highly Potent and Selective Dipeptidyl Peptidase-4 Inhibitors

被引：7

作者：

Jiang, Tao ^{[1
]}

Zhou, Yuren ^{[1
]}

Zhu, Jianming ^{[1
]}

Chen, Zhuxi ^{[1
]}

Sun, Peng ^{[1
]}

Zhang, Qiang ^{[1
]}

Wang, Zhen ^{[1
]}

Shao, Qiang ^{[1
]}

Jiang, Xiangrui ^{[1
]}

Li, Bo ^{[1
]}

Wang, Heyao ^{[1
]}

Zhu, Weiliang ^{[1
]}

Shen, Jingshan ^{[1
]}

机构：

[1] Chinese Acad Sci, Shanghai Inst Mat Med, Key Lab Receptor Res, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China

来源：

ARCHIV DER PHARMAZIE | 2015年 / 348卷 / 06期

基金：

中国国家自然科学基金;

关键词：

beta-Homophenylalanine; DPP-4; Drug design; Inhibitors; P2-binding moiety; IV INHIBITOR; DISCOVERY;

D O I：

10.1002/ardp.201500082

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The optimization of a series of fused -homophenylalanine inhibitors of dipeptidyl peptidase-4 (DPP-4) is described. Modification on the P2-binding moiety of 6 (IC50=10nM) led to the discovery of -homophenylalanine derivatives containing pyrrolidin-2-ylmethyl amides. The introduction of a sulfamine in the meta position of the phenyl ring improved the potency against DPP-4 (6-12-fold increase). Compound 14k showed DPP-4 inhibitory activity with an IC50 value of 0.87nM. Meanwhile, in vivo experiments exhibited that 14h had an efficiency comparable to sitagliptin at the dose of 10mg/kg.

引用

页码：399 / 407

页数：9

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