Discovery of a Novel Glucagon Receptor Antagonist N-[(4-{(1S)-1-[3-(3, 5-Dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl]ethyl}phenyl)carbonyl]-尾-alanine (MK-0893) fo

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• 作者：Yusheng Xiong ; Jian Guo ; Mari R. Candelore ; Rui Liang ; Corey Miller ; Qing Dallas-Yang ; Guoqiang Jiang ; Peggy E. McCann ; Sajjad A. Qureshi ; Xinchun Tong ; Shiyao Sherrie Xu ; Jackie Shang ; Stella H. Vincent ; Laurie M. Tota ; Michael J. Wright ; Xiaodong Yang ; Bei B. Zhang ; James R. Tata ; Emma R. Parmee
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：July 12, 2012
• 年：2012
• 卷：55
• 期：13
• 页码：6137-6148
• 全文大小：442K
• 年卷期：v.55,no.13(July 12, 2012)
• ISSN：1520-4804

文摘

A potent, selective glucagon receptor antagonist 9m, N-[(4-{(1S)-1-[3-(3,5-dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl]ethyl}phenyl)carbonyl]-尾-alanine, was discovered by optimization of a previously identified lead. Compound 9m is a reversible and competitive antagonist with high binding affinity (IC₅₀ of 6.6 nM) and functional cAMP activity (IC₅₀ of 15.7 nM). It is selective for glucagon receptor relative to other family B GPCRs, showing IC₅₀ values of 1020 nM for GIPR, 9200 nM for PAC1, and >10000 nM for GLP-1R, VPAC1, and VPAC2. Compound 9m blunted glucagon-induced glucose elevation in hGCGR mice and rhesus monkeys. It also lowered ambient glucose levels in both acute and chronic mouse models: in hGCGR ob/ob mice it reduced glucose (AUC 0鈥? h) by 32% and 39% at 3 and 10 mpk single doses, respectively. In hGCGR mice on a high fat diet, compound 9m at 3, and 10 mpk po in feed lowered blood glucose levels by 89% and 94% at day 10, respectively, relative to the difference between the vehicle control and lean hGCGR mice. On the basis of its favorable biological and DMPK properties, compound 9m (MK-0893) was selected for further preclinical and clinical evaluations.