Discovery and optimization of 5-fluoro-4,6-dialkoxypyrimidine GPR119 agonists

被引：9

作者：

Buzard, Daniel J. ^{[1
]}

Kim, Sun Hee ^{[1
]}

Lehmann, Juerg ^{[1
]}

Han, Sangdon ^{[1
]}

Calderon, Imelda ^{[1
]}

Wong, Amy ^{[1
]}

Kawasaki, Andrew ^{[1
]}

Narayanan, Sanju ^{[1
]}

Bhat, Rohit ^{[1
]}

Gharbaoui, Tawfik ^{[1
]}

Lopez, Luis ^{[1
]}

Yue, Dawei ^{[1
]}

Whelan, Kevin ^{[1
]}

Al-Shamma, Hussien ^{[1
]}

Unett, David J. ^{[1
]}

Shu, Hsin-Hui ^{[1
]}

Tung, Shiu-Feng ^{[1
]}

Chang, Steve ^{[1
]}

Chuang, Ching-Fen ^{[1
]}

Morgan, Michael ^{[1
]}

Sadeque, Abu ^{[1
]}

Chu, Zhi-Liang ^{[1
]}

Leonard, James N. ^{[1
]}

Jones, Robert M. ^{[1
]}

机构：

[1] Arena Pharmaceut Inc, San Diego, CA 92121 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2014年 / 24卷 / 17期

关键词：

GPR119; GDIR; APD597; Diabetes; GLYCEMIC CONTROL; G-PROTEIN-COUPLED-RECEPTOR-119; RELEASE;

D O I：

10.1016/j.bmcl.2014.06.071

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of 5-fluoro-4,6-dialkoxypyrimidine GPR119 modulators were discovered and optimized for in vitro agonist activity. A lead molecule was identified that has improved agonist efficacy relative to our clinical compound (APD597) and possesses reduced CYP2C9 inhibitory potential. This optimized lead was found to be efficacious in rodent models of glucose control both alone and in combination with a Dipeptidyl peptidase-4 (DPP-4) inhibitor. (C) 2014 Elsevier Ltd. All rights reserved.

引用

页码：4332 / 4335

页数：4

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