ABSTRACT
A novel class of 1,3,5-pyrazoles has been discovered as potent human glucagon receptor antagonists. Notably, compound 26 is orally bioavailable in several preclinical species and shows selectivity towards cardiac ion channels, other family B receptors such hGIP and hGLP1, and a large panel of enzymes and additional receptors. When dosed orally, compound 26 is efficacious in suppressing glucagon induced plasma glucose excursion in rhesus monkey and transgenic murine pharmacodynamic models at 1 and 10 mpk, respectively.
Subject(s)
Pyrazoles/chemistry , Receptors, Glucagon/antagonists & inhibitors , Administration, Oral , Animals , Blood Glucose/metabolism , Dogs , Drug Evaluation, Preclinical , Humans , Macaca mulatta , Mice , Mice, Transgenic , Pyrazoles/chemical synthesis , Pyrazoles/pharmacokinetics , Rats , Receptors, Glucagon/metabolism , Structure-Activity RelationshipABSTRACT
A series of conformationally constrained tri-substituted ureas were synthesized, and their potential as glucagon receptor antagonists was evaluated. This effort resulted in the identification of compound 4a, which had a binding IC50 of 4.0 nM and was shown to reduce blood glucose levels at 3 mg/kg in glucagon-challenged mice containing a humanized glucagon receptor. Compound 4a was efficacious in correcting hyperglycemia induced by a high fat diet in transgenic mice at an oral dose as low as 3 mg/kg.
Subject(s)
Receptors, Glucagon/antagonists & inhibitors , Urea/analogs & derivatives , Urea/chemical synthesis , Animals , Blood Glucose/metabolism , CHO Cells , Chromatography, High Pressure Liquid , Cricetinae , Cricetulus , Cyclic AMP/metabolism , Dietary Fats , Drug Design , Gastric Inhibitory Polypeptide/metabolism , Glucagon/antagonists & inhibitors , Half-Life , Humans , Hyperglycemia/chemically induced , Hyperglycemia/prevention & control , Indicators and Reagents , Mice , Mice, Transgenic , Molecular Conformation , Receptors, Glucagon/genetics , Urea/pharmacologyABSTRACT
A novel class of spiro-ureas has been discovered as potent human glucagon receptor antagonists in both binding and functional assays. Preliminary studies have revealed that compound 15 is an orally active human glucagon receptor antagonist in a transgenic murine pharmacodynamic model at 10 and 30 mpk. Compound 15 is orally bioavailable in several preclinical species and shows selectivity toward cardiac ion channels and other family B receptors, such as hGIP1 and hGLP.
