| Literature DB >> 24900757 |
Ming Yu1, Mike Lizarzaburu1, Alykhan Motani1, Zice Fu1, Xiaohui Du1, Jiwen Jim Liu1, Xianyun Jiao1, SuJen Lai1, Peter Fan1, Angela Fu1, Qingxiang Liu1, Michiko Murakoshi2, Futoshi Nara2, Kozo Oda2, Ryo Okuyama2, Jeff D Reagan1, Nobuaki Watanabe2, Mami Yamazaki2, Yumei Xiong1, Ying Zhang1, Run Zhuang1, Daniel C-H Lin1, Jonathan B Houze1, Julio C Medina1, Leping Li1.
Abstract
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.Entities:
Keywords: GPR142 agonist; aminopyrazole−phenylalanine; human islet transplant; insulin secretagogue; oral glucose tolerance test; prodrug; type 2 diabetes
Year: 2013 PMID： 24900757 PMCID： PMC4027463 DOI： 10.1021/ml4000854
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345