The design and synthesis of a potent glucagon receptor antagonist with favorable physicochemical and pharmacokinetic properties as a candidate for the treatment of type 2 diabetes mellitus

被引：36

作者：

Guzman-Perez, Angel ^{[1
]}

Pfefferkorn, Jeffrey A. ^{[1
]}

Lee, Esther C. Y. ^{[1
]}

Stevens, Benjamin D. ^{[1
]}

Aspnes, Gary E. ^{[1
]}

Bian, Jianwei ^{[1
]}

Didiuk, Mary T. ^{[1
]}

Filipski, Kevin J. ^{[1
]}

Moore, Dianna ^{[1
]}

Perreault, Christian ^{[1
]}

Sammons, Matthew F. ^{[1
]}

Tu, Meihua ^{[1
]}

Brown, Janice ^{[1
]}

Atkinson, Karen ^{[1
]}

Litchfield, John ^{[1
]}

Tan, Beijing ^{[1
]}

Samas, Brian ^{[1
]}

Zavadoski, William J. ^{[1
]}

Salatto, Christopher T. ^{[1
]}

Treadway, Judith ^{[1
]}

机构：

[1] Pfizer Wordwide Res & Dev, Groton, CT 06442 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2013年 / 23卷 / 10期

关键词：

Glucagon receptor antagonist; Diabetes mellitus; Physicochemical properties; VIVO TOXICOLOGICAL OUTCOMES; ARYL HALIDES; ASSAY;

D O I：

10.1016/j.bmcl.2013.03.014

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A novel and potent small molecule glucagon receptor antagonist for the treatment of diabetes mellitus is reported. This candidate, (S)-3-[4-(1-{3,5-dimethyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenoxy}butyl)benzamido]propanoic acid, has lower molecular weight and lipophilicity than historical glucagon receptor antagonists, resulting in excellent selectivity in broad-panel screening, lower cytotoxicity, and excellent overall in vivo safety in early pre-clinical testing. Additionally, it displays low in vivo clearance and excellent oral bioavailability in both rats and dogs. In a rat glucagon challenge model, it was shown to reduce the glucagon-elicited glucose excursion in a dose-dependent manner and at a concentration consistent with its rat in vitro potency. Its properties make it an excellent candidate for further investigation. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：3051 / 3058

页数：8

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