Data_Sheet_1_Chemistry and Hypoglycemic Activity of GPR119 Agonist ZB-16.docx (889.86 kB)

Data_Sheet_1_Chemistry and Hypoglycemic Activity of GPR119 Agonist ZB-16.docx

Download (889.86 kB)
dataset
posted on 19.09.2018, 04:04 by Ivan N. Tyurenkov, Denis V. Kurkin, Dmitry A. Bakulin, Elena V. Volotova, Evgeny I. Morkovin, Mikhail A. Chafeev, Ruben N. Karapetian

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.

History

Licence

Exports

Logo branding

Licence

Exports