Optimization of a novel series of potent and orally bioavailable GPR119 agonists

Abstract We describe the discovery and optimization of a novel series of furo[3,2- d ]pyrimidines as G protein-coupled receptor 119 agonists. Agonistic activity of 4 (EC 50  = 129 nM) was improved by replacing the intramolecular hydrogen bond between the fluorine atom and the aniline hydrogen in the head moiety with a covalent C-C bond to enhance conformational restriction, which consequently gave a lead compound 12 (EC 50  = 53 nM). Optimized compound 26 , which was identified by the further optimization of 12 , exhibited potent activity (EC 50  = 42 nM) with improved clearance in liver microsomes and induced a 33% reduction in blood glucose area under the curve at a dose of 10 mg/kg in an oral glucose tolerance test in C57BL/6N mice.