Synthesis and structure-activity relationships of potent 3- or 4-substituted-2-cyanopyrrolidine dipeptidyl peptidase IV inhibitors

被引：43

作者：

Fukushima, H ^{[1
]}

Hiratate, A ^{[1
]}

Takahashi, M ^{[1
]}

Saito, M ^{[1
]}

Munetomo, E ^{[1
]}

Kitano, K ^{[1
]}

Saito, H ^{[1
]}

Takaoka, Y ^{[1
]}

Yamamoto, K ^{[1
]}

机构：

[1] Taisho Pharmaceut Co Ltd, Med Res Labs, Kita Ku, Saitama 3319530, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2004年 / 12卷 / 23期

关键词：

dipeptidyl peptidase IV; inhibitor; fluoropyrrolidine; diabetes;

D O I：

10.1016/j.bmc.2004.09.010

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Dipeptidyl peptidase IV (DPP-IV) inhibitors have attracted attention as potential drugs for use in the treatment of type 2 diabetes because they prevent degradation of glucagon-like peptide-1 (GLP- 1) and extend its duration of action. A series of 2-cyanopyrrolidines are among the most potent of DPP-IV inhibitors. We focused our attention on substitutions at the 3- or 4-position of 2-cyanopyrrolidines and synthesized and evaluated various derivatives. Among them, the 4-fluoro derivative was found to exhibit better DPP-IV inhibitory activity and higher plasma drug concentrations after oral administration to rats than the 4-unsubstituted derivative. We report here on the synthesis and biological data of the aforementioned derivatives. (C) 2004 Elsevier Ltd. All rights reserved.

引用

页码：6053 / 6061

页数：9

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