Discovery of novel spiro[chromane-2, 4′-piperidine] derivatives as potent and orally bioavailable G-protein-coupled receptor 119 agonists. Issue 19 (15th October 2018) - Koshizawa, Tomoaki
Graphical abstract: Highlights: The spiro-type scaffold was used as a novel linker-to-tail moiety of GPR119 agonists. The rigid spiro-type scaffold enabled flexible and successful optimization. Optimized( R )-29 exhibited a potent in vivo activity sufficient for a drug candidate. Abstract: Herein, we describe the discovery, synthesis, and evaluation of a novel series of spiro[chromane-2, 4′-piperidine] derivatives as G-protein-coupled receptor 119 agonists. Their initial design exploited the conformational restriction in the linker-to-tail moiety, which was a key concept in this study, to give lead compound11 (EC50 = 369 nM, E max = 82%). An extensive structure–activity relationship study resulted in the identification of the optimized drug candidate( R )-29 (EC50 = 54 nM, E max = 181%). The defining structural features of the series were a terminal benzyl-type bulky substituent and a methylene linker between the sulfonyl and phenyl groups, both of which were in the head moiety as well as the spiro-type scaffold in the linker-to-tail moiety. An in vivo oral glucose-tolerance test using C57BL/6N mice showed that( R )-29 reduced glucose excursion at a dose of 3 mg/kg in a dose-dependent manner.