Identification and SAR of Glycine Benzamides as Potent Agonists for the GPR139 Receptor

ACS Med Chem Lett. 2015 Jul 20;6(9):1015-8. doi: 10.1021/acsmedchemlett.5b00247. eCollection 2015 Sep 10.


A focused high throughput screening for GPR139 was completed for a select 100K compounds, and new agonist leads were identified. Subsequent analysis and structure-activity relationship studies identified (S)-3-chloro-N-(2-oxo-2-((1-phenylethyl)amino)ethyl)benzamide 7c as a potent and selective agonist of hGPR139 with an EC50 = 16 nM. The compound was found to cross the blood-brain barrier and have good drug-like properties amenable for oral dosing in rat.

Keywords: GPR139; Orphan receptors; agonists; glycine amides.