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 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.
