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Aminopyrazole–Phenylalanine Based GPR142 Agonists: Discovery of Tool Compound and in Vivo Efficacy Studies

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journal contribution
posted on 12.09.2013, 00:00 by Ming Yu, Mike Lizarzaburu, Alykhan Motani, Zice Fu, Xiaohui Du, Jiwen (Jim) Liu, Xianyun Jiao, SuJen Lai, Peter Fan, Angela Fu, Qingxiang Liu, Michiko Murakoshi, Futoshi Nara, Kozo Oda, Ryo Okuyama, Jeff D. Reagan, Nobuaki Watanabe, Mami Yamazaki, Yumei Xiong, Ying Zhang, Run Zhuang, Daniel C.-H. Lin, Jonathan B. Houze, Julio C. Medina, Leping Li
Herein, we report the lead optimization of amrinone–phenylalanine based GPR142 agonists. Structure–activity relationship studies led to the discovery of aminopyrazole–phenylalanine carboxylic acid 22, which exhibited good agonistic activity, high target selectivity, desirable pharmacokinetic properties, and no cytochrome P450 or hERG liability. Compound 22, together with its orally bioavailable ethyl ester prodrug 23, were found to be suitable for in vivo proof-of-concept studies. Compound 23 displayed good efficacy in a mouse oral glucose tolerance test (OGTT). Compound 22 showed GPR142 dependent stimulation of insulin secretion in isolated mouse islets and demonstrated a statistically significant glucose lowering effect in a mouse model bearing transplanted human islets.