Details

Autor(en) / Beteiligte

• Yu, Ming
• Lizarzaburu, Mike
• Motani, Alykhan
• Fu, Zice
• Du, Xiaohui
• Liu, Jiwen (Jim)
• Jiao, Xianyun
• Lai, SuJen
• Fan, Peter
• Fu, Angela
• Liu, Qingxiang
• Murakoshi, Michiko
• Nara, Futoshi
• Oda, Kozo
• Okuyama, Ryo
• Reagan, Jeff D
• Watanabe, Nobuaki
• Yamazaki, Mami
• Xiong, Yumei
• Zhang, Ying
• Zhuang, Run
• Lin, Daniel C.-H
• Houze, Jonathan B
• Medina, Julio C
• Li, Leping

Titel

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

Ist Teil von

• ACS medicinal chemistry letters, 2013-09, Vol.4 (9), p.829-834

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2013

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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.