Discovery of phenyl acetamides as potent and selective GPR119 agonists.

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. Copyright © 2017 Elsevier Ltd. All rights reserved.

Citation

Cheng Zhu, Liping Wang, Yuping Zhu, Zack Zhiqiang Guo, Ping Liu, Zhiyong Hu, Jason W Szewczyk, Ling Kang, Gary Chicchi, Anka Ehrhardt, Andrea Woods, Toru Seo, Morgan Woods, Margaret van Heek, Karen H Dingley, Jianmei Pang, Gino M Salituro, Joyce Powell, Jenna L Terebetski, Viktor Hornak, Louis-Charles Campeau, Robert K Orr, Feroze Ujjainwalla, Michael Miller, Andrew Stamford, Harold B Wood, Timothy Kowalski, Ravi P Nargund, Scott D Edmondson. Discovery of phenyl acetamides as potent and selective GPR119 agonists. Bioorganic & medicinal chemistry letters. 2017 Mar 01;27(5):1124-1128

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PMID: 28185720

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