Discovery, structure-activity relationship, and pharmacological evaluation of (5-substituted-pyrrolidinyl-2-carbonyl)-2-cyanopyrrolidines as potent dipeptidyl peptidase IV inhibitors

被引:64
作者
Pei, Zhonghua
Li, Xiaofeng
Longenecker, Kenton
von Geldern, Thomas W.
Wiedeman, Paul E.
Lubben, Thomas H.
Zinker, Bradley A.
Stewart, Kent
Ballaron, Stephen J.
Stashko, Michael A.
Mika, Amanda K.
Beno, David W. A.
Long, Michelle
Wells, Heidi
Kempf-Grote, Anita J.
Madar, David J.
McDermott, Todd S.
Bhagavatula, Lakshmi
Fickes, Michael G.
Pireh, Daisy
Solomon, Larry R.
Lake, Marc R.
Edalji, Rohinton
Fry, Elizabeth H.
Sham, Hing L.
Trevillyan, James M.
机构
[1] Abbott Labs, Metab Dis Res, Adv Technol,Global Pharmaceut Res & Dev, Dept Exploratory Pharmacokinet & Pharmaceut, Abbott Pk, IL 60064 USA
[2] Abbott Labs, Dept Proc Chem, Global Pharmaceut Res & Dev, Abbott Pk, IL 60064 USA
关键词
D O I
10.1021/jm051283e
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
A series of ( 5-substituted pyrrolidinyl-2-carbonyl)-2-cyanopyrrolidine ( C5-Pro-Pro) analogues was discovered as dipeptidyl peptidase IV ( DPPIV) inhibitors as a potential treatment of diabetes and obesity. X-ray crystallography data show that these inhibitors bind to the catalytic site of DPPIV with the cyano group forming a covalent bond with the serine residue of DPPIV. The C5-substituents make various interactions with the enzyme and affect potency, chemical stability, selectivity, and PK properties of the inhibitors. Optimized analogues are extremely potent with subnanomolar K-i's, are chemically stable, show very little potency decrease in the presence of plasma, and exhibit more than 1,000-fold selectivity against related peptidases. The best compounds also possess good PK and are efficacious in lowering blood glucose in an oral glucose tolerance test in ZDF rats.
引用
收藏
页码:3520 / 3535
页数:16
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