Discovery of a Novel GlucagonReceptor 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.

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, wasdiscovered by optimization of a previously identified lead. Compound 9mis a reversible and competitive antagonist with high bindingaffinity (IC50of 6.6 nM) and functional cAMP activity(IC50of 15.7 nM). It is selective for glucagon receptorrelative to other family B GPCRs, showing IC50values of1020 nM for GIPR, 9200 nM for PAC1, and >10000 nM for GLP-1R, VPAC1,and VPAC2. Compound 9mblunted glucagon-induced glucoseelevation in hGCGR mice and rhesus monkeys. It also lowered ambientglucose levels in both acute and chronic mouse models: in hGCGR ob/obmice it reduced glucose (AUC 0–6 h) by 32% and 39% at 3 and10 mpk single doses, respectively. In hGCGR mice on a high fat diet,compound 9mat 3, and 10 mpk po in feed lowered bloodglucose levels by 89% and 94% at day 10, respectively, relative tothe difference between the vehicle control and lean hGCGR mice. Onthe basis of its favorable biological and DMPK properties, compound 9m(MK-0893) was selected for further preclinical and clinicalevaluations. [ABSTRACT FROM AUTHOR]