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.
MeSH terms
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Animals
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Area Under Curve
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Blood Glucose / metabolism*
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CHO Cells
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Cricetinae
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Cricetulus
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Diabetes Mellitus, Type 2 / drug therapy*
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Diet, High-Fat / adverse effects
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Disease Models, Animal
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Dogs
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Glucagon / metabolism*
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Glucagon-Like Peptide-1 Receptor
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Humans
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Inhibitory Concentration 50
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Macaca mulatta
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Mice
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Mice, Obese
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Microsomes, Liver / metabolism
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Pyrazoles / chemistry
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Pyrazoles / pharmacology*
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Pyrazoles / therapeutic use
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Rats
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Receptors, Gastrointestinal Hormone / antagonists & inhibitors
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Receptors, Glucagon / antagonists & inhibitors*
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Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / antagonists & inhibitors
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Receptors, Vasoactive Intestinal Peptide, Type II / antagonists & inhibitors
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Receptors, Vasoactive Intestinal Polypeptide, Type I / antagonists & inhibitors
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beta-Alanine / analogs & derivatives*
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beta-Alanine / chemistry
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beta-Alanine / pharmacology
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beta-Alanine / therapeutic use
Substances
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Blood Glucose
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GLP1R protein, human
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Glp1r protein, mouse
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Glp1r protein, rat
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Glucagon-Like Peptide-1 Receptor
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Pyrazoles
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Receptors, Gastrointestinal Hormone
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Receptors, Glucagon
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Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I
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Receptors, Vasoactive Intestinal Peptide, Type II
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Receptors, Vasoactive Intestinal Polypeptide, Type I
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beta-Alanine
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pyrazole
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Glucagon
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N-((4-(1-(3-(3,5-dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl)ethyl)phenyl)carbonyl)-beta-alanine
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gastric inhibitory polypeptide receptor