Discovery of Nonpeptide, Orally Available Small Molecule GLP-1 Receptor Agonists

GLP-1R agonists comprise a growing class of agents that deliver unprecedented efficacy in the treatment of diabetes. We discovered promising compounds for the development of a novel small molecule GLP-1R agonist and examined their efficacy in cynomolgus monkey. The in vitro activities of the compounds were evaluated by measuring cAMP accumulation in cells expressing human GLP-1R. All compounds demonstrated potent cAMP accumulation of EC50 value below 20 nM, with one compound showing 1.5 nM. In addition, the compounds showed excellent selectivity against related class B GPCR, with no stimulatory activity on human GIP, GCG, and GLP-2 receptors. In the intravenous glucose tolerance test, according to the present disclosure, the compounds increased insulin secretion in cynomolgus monkey (dosed 50 mg/kg, p.o.), demonstrating their efficacy as orally available GLP-1 receptor agonists. Moreover, inhibitory effect on the hERG current was investigated and the compounds were shown to have favorable safety profile with IC50 values ranging from 34.6 to more than 100 μM. In conclusion, we discovered promising compounds which have potential to be developed as an orally active, non-peptide GLP-1R agonist for the treatment of type 2 diabetes with favorable safety profile regarding the hERG current. Disclosure A. Im: None. Y. Jun: None. E. Jang: None. Y. Yoo: None. W. Jeon: None. K. An: None. J. Park: None. D. Hong: None. I. Je: None. J. Kim: None. M. Chang: None. C. Hong: None. J. Shin: None. T. Sohn: None.