Discovery of structurally novel, potent and orally efficacious GPR119 agonists

被引：11

作者：

Alper, Phil ^{[1
]}

Azimioara, Mihai ^{[1
]}

Cow, Christopher ^{[1
]}

Mutnick, Daniel ^{[1
]}

Nikulin, Victor ^{[1
]}

Michellys, Pierre-Yves ^{[1
]}

Wang, Zhiliang ^{[1
]}

Reding, Esther ^{[1
]}

Paliotti, Michael ^{[1
]}

Li, Jing ^{[1
]}

Bao, Dingjiu ^{[1
]}

Zoll, Jocelyn ^{[1
]}

Kim, Young ^{[1
]}

Zimmerman, Matthew ^{[1
]}

Groessel, Todd ^{[1
]}

Tuntland, Tove ^{[1
]}

Joseph, Sean B. ^{[1
]}

McNamara, Peter ^{[1
]}

Seidel, H. Martin ^{[1
]}

Epple, Robert ^{[1
]}

机构：

[1] Novartis Res Fdn, Genom Inst, San Diego, CA 92121 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2014年 / 24卷 / 10期

关键词：

GPCR agonists; PR119; Pyrazolopyrimidines; Type; 2; diabetes; PROTEIN-COUPLED RECEPTOR; AGENTS;

D O I：

10.1016/j.bmcl.2014.03.023

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Screening hit 5 was identified in a biochemical screen for GPR119 agonists. Compound 5 was structurally novel, displayed modest biochemical activity and no oral exposure, but was structurally distinct from typical GPR119 agonist scaffolds. Systematic optimization led to compound 36 with significantly improved in vitro activity and oral exposure, to elevate GLP1 acutely in an in vivo mouse model at a dose of 10 mg/kg. (C) 2014 Elsevier Ltd. All rights reserved.

引用

页码：2383 / 2387

页数：5