AUTHOR=Tyurenkov Ivan N. , Kurkin Denis V. , Bakulin Dmitry A. , Volotova Elena V. , Morkovin Evgeny I. , Chafeev Mikhail A. , Karapetian Ruben N. TITLE=Chemistry and Hypoglycemic Activity of GPR119 Agonist ZB-16 JOURNAL=Frontiers in Endocrinology VOLUME=9 YEAR=2018 URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2018.00543 DOI=10.3389/fendo.2018.00543 ISSN=1664-2392 ABSTRACT=

This article is to highlight the chemical properties and primary pharmacology of novel GPR119 agonist ZB-16 and its analogs, which were rejected during the screening. Experiments were performed in vitro (specific activity, metabolism and cell toxicity) and in vivo (hypoglycemic activity and pharmacokinetics). ZB-16 exhibits nanomolar activity (EC50 = 7.3–9.7 nM) on target receptor GPR119 in vitro associated with hypoglycemic activity in vivo. In animals with streptozotocin-nicotinamide induced type 2 diabetes mellitus (STZ-NA T2D) daily oral dose of ZB-16 (1 mg/kg) or sitagliptin (10 mg/kg) for 28 days resulted in the reduction of blood glucose levels. The effects of ZB-16 were comparable to the hypoglycemic action of sitagliptin. ZB-16 demonstrated relatively low plasma exposition, high distribution volume, mild clearance and a prolonged half-life (more than 12 h). The present study demonstrates that the targeted search for selective GPR119 receptor agonists is a well-founded approach for developing novel drugs for the therapy of T2D. Based on the combination of high in vitro activity (compared to competitor standards), a useful ADME profile, distinct hypoglycemic activity which is comparable to the efficacy of sitagliptin in rats with experimental T2D, and the acceptable pharmacokinetic profile, we recommend the ZB-16 compound for further research.