2. Academic Validation
  3. 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]-β-alanine (MK-0893) for the treatment of type II diabetes

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]-β-alanine (MK-0893) for the treatment of type II diabetes

  • J Med Chem. 2012 Jul 12;55(13):6137-48. doi: 10.1021/jm300579z.
Yusheng Xiong 1,  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
Affiliations

Affiliation

  • 1 Discovery and Preclinical Sciences, Merck Research Laboratories, Rahway, NJ 07065, USA. yusheng_xiong@merck.com
PMID: 22708876 DOI: 10.1021/jm300579z
Abstract

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]-β-alanine, was discovered by optimization of a previously identified lead. Compound 9m is a reversible and competitive antagonist with high binding affinity (IC(50) of 6.6 nM) and functional cAMP activity (IC(50) of 15.7 nM). It is selective for Glucagon Receptor relative to Other family B GPCRs, showing IC(50) 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 0-6 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.

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