| Autor: |
Jeff D. Reagan, Julio C. Medina, Xianyun Jiao, Leping Li, Run Zhuang, Mami Yamazaki, Mike Lizarzaburu, Sujen Lai, Jonathan B. Houze, Jiwen Jim Liu, Daniel C.-H. Lin, Alykhan Motani, Ryo Okuyama, Peter Fan, Ying Zhang, Futoshi Nara, Michiko Murakoshi, Angela Fu, Nobuaki Watanabe, Yumei Xiong, Zice Fu, Xiaohui Du, Qingxiang Liu, Ming Yu, Kozo Oda |
| Rok vydání: |
2013 |
| Předmět: |
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| Zdroj: |
ACS medicinal chemistry letters. 4(9) |
| ISSN: |
1948-5875 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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