Discovery of novel, potent, and orally active spiro-urea human glucagon receptor antagonists

The discovery and SAR study of a novel spiro-urea series of human glucagon receptor antagonists such as 15 are presented. 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.