Design and synthesis of DPP-IV inhibitors lacking the electrophilic nitrile group

被引：27

作者：

Kondo, Takashi ^{[1
]}

Nekado, Takahiro ^{[1
]}

Sugimoto, Isamu ^{[1
]}

Ochi, Kenya ^{[1
]}

Takai, Shigeyuki ^{[1
]}

Kinoshita, Atsushi ^{[1
]}

Hatayama, Akira ^{[1
]}

Yamamoto, Susumu ^{[1
]}

Kishikawa, Katsuya ^{[1
]}

Nakai, Hisao ^{[1
]}

Toda, Masaaki ^{[1
]}

机构：

[1] Ono Pharmaceut Co Ltd, Minase Res Inst, Osaka 6188585, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2008年 / 16卷 / 04期

关键词：

DPP-IV inhibitor; (4 beta-substituted)-L-prolylpyrrolidine; 1,2,4-thiadiazol-5-yl-piperazine;

D O I：

10.1016/j.bmc.2007.11.031

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：

A series of (4 beta-substituted)-L-prolylpyrrolidine analogs lacking the electrophilic nitrile function were synthesized and their dipeptidyl peptidase IV (DPP-IV) inhibitory activity and duration of ex vivo activity were evaluated. Structural optimization of a N-(3-phenyl-1,2,4-thiadiazol-5-yl) piperazine analog 8, which was found by high-speed analog synthesis, was carried out to improve the potency and duration of action. A representative compound 26 was evaluated to assess its effect on the plasma glucose level after the oGTT (oral glucose tolerance test) in normal rats. Structure-activity relationships (SAR) are also presented. (C) 2007 Elsevier Ltd. All rights reserved.

引用

页码：1613 / 1631

页数：19

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