5 years ago

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

Optimization of a novel series of potent and orally bioavailable GPR119 agonists
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 (EC50 =129nM) 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 (EC50 =53nM). Optimized compound 26, which was identified by the further optimization of 12, exhibited potent activity (EC50 =42nM) with improved clearance in liver microsomes and induced a 33% reduction in blood glucose area under the curve at a dose of 10mg/kg in an oral glucose tolerance test in C57BL/6N mice.

Publisher URL: www.sciencedirect.com/science

DOI: S0960894X17306364

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