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Pyrrolidine-constrained phenethylamines: The design of potent, selective, and pharmacologically efficacious dipeptidyl peptidase IV (DPP4) inhibitors from a lead-like screening hit

被引：33
作者：
Backes, Bradley J.
Longenecker, Kenton
Hamilton, Gregory L.
Stewart, Kent
Lai, Chunqiu
Kopecka, Hana
von Geldern, Thomas W.
Madar, David J.
Pei, Zhonghua
Lubben, Thomas H.
Zinker, Bradley A.
Tian, Zhenping
Ballaron, Stephen J.
Stashko, Michael A.
Mika, Amanda K.
Beno, David W. A.
Kempf-Grote, Anita J.
Black-Schaefer, Candace
Sham, Hing L.
Trevillyan, James M.
机构：
[1] Abbott Labs, Dept Exploratory Pharmacokinet, Abbott Pk, IL 60064 USA
[2] Abbott Labs, Dept Pharmaceut, Abbott Pk, IL 60064 USA
来源：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2007年 / 17卷 / 07期
关键词：
DPPIV inhibitors; diabetes; structure-based design;
D O I：
10.1016/j.bmcl.2007.01.026
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
A novel series of pyrrolidine-constrained phenethylamines were developed as dipeptidyl peptidase IV (DPP4) inhibitors for the treatment of type 2 diabetes. The cyclohexene ring of lead-like screening hit 5 was replaced with a pyrrolidine to enable parallel chemistry, and protein co-crystal structural data guided the optimization of N-substituents. Employing this strategy, a > 400x improvement in potency over the initial hit was realized in rapid fashion. Optimized compounds are potent and selective inhibitors with excellent pharmacokinetic profiles. Compound 30 was efficacious in vivo, lowering blood glucose in ZDF rats that were allowed to feed freely on a mixed meal. (c) 2007 Elsevier Ltd. All rights reserved.
引用
收藏
页码：2005 / 2012
页数：8
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