Discovery of phenyl acetamides as potent and selective GPR119 agonists

被引：8

作者：

Zhu, Cheng ^{[1
]}

Wang, Liping ^{[2
]}

Zhu, Yuping ^{[1
]}

Guo, Zack Zhiqiang ^{[2
]}

Liu, Ping ^{[1
]}

Hu, Zhiyong ^{[1
]}

Szewczyk, Jason W. ^{[2
]}

Kang, Ling ^{[2
]}

Chicchi, Gary ^{[2
]}

Ehrhardt, Anka ^{[2
]}

Woods, Andrea ^{[2
]}

Seo, Toru ^{[2
]}

Woods, Morgan ^{[1
]}

van Heek, Margaret ^{[1
]}

Dingley, Karen H. ^{[1
]}

Pang, Jianmei ^{[1
]}

Salituro, Gino M. ^{[2
]}

Powell, Joyce ^{[2
]}

Terebetski, Jenna L. ^{[1
]}

Hornak, Viktor ^{[2
]}

Campeau, Louis-Charles ^{[2
]}

Orr, Robert K. ^{[2
]}

Ujjainwalla, Feroze ^{[1
]}

Miller, Michael ^{[1
]}

Stamford, Andrew ^{[2
]}

Wood, Harold B. ^{[1
]}

Kowalski, Timothy ^{[1
]}

Nargund, Ravi P. ^{[1
]}

Edmondson, Scott D. ^{[1
]}

机构：

[1] Merck & Co Inc, Early Dev & Discovery Sci, 2000 Galloping Hill Rd, Kenilworth, NJ 07033 USA

[2] Merck & Co Inc, Early Dev & Discovery Sci, 126 East Lincoln Ave, Rahway, NJ 07065 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2017年 / 27卷 / 05期

关键词：

GPR119; agonist; Type; 2; diabetes; Phenyl acetamide; Cis cyclopropane; Glucose dependent insulin secretion; GLYCEMIC CONTROL; IN-VITRO; DESIGN; SERIES; OPTIMIZATION; RELEASE; DRUGS;

D O I：

10.1016/j.bmcl.2017.01.091

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The paper describes the SAR/SPR studies that led to the discovery of phenoxy cyclopropyl phenyl acetamide derivatives as potent and selective GPR119 agonists. Based on a cis cyclopropane scaffold discovered previously, phenyl acetamides such as compound 17 were found to have excellent GPR119 potency and improved physicochemical properties. Pharmacokinetic data of compound 17 in rat, dog and rhesus will be described. Compound 17 was suitable for QD dosing based on its predicted human half-life, and its projected human dose was much lower than that of the recently reported structurally-related benzyloxy compound 2. Compound 17 was selected as a tool compound candidate for NHP (Non-Human Primate) efficacy studies. (C) 2017 Elsevier Ltd. All rights reserved.

引用

页码：1124 / 1128

页数：5

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