BMS-986163, a Negative Allosteric Modulator of GluN2B with Potential Utility in Major Depressive Disorder.

There is a significant unmet medical need for more efficacious and rapidly acting antidepressants. Toward this end, negative allosteric modulators of the -methyl-d-aspartate receptor subtype GluN2B have demonstrated encouraging therapeutic potential. We report herein the discovery and preclinical profile of a water-soluble intravenous prodrug BMS-986163 () and its active parent molecule BMS-986169 (), which demonstrated high binding affinity for the GluN2B allosteric site ( = 4.0 nM) and selective inhibition of GluN2B receptor function (IC = 24 nM) in cells. The conversion of prodrug to parent was rapid in vitro and in vivo across preclinical species. After intravenous administration, compounds and have exhibited robust levels of ex vivo GluN2B target engagement in rodents and antidepressant-like activity in mice. No significant off-target activity was observed for , , or the major circulating metabolites and . The prodrug BMS-986163 () has demonstrated an acceptable safety and toxicology profile and was selected as a preclinical candidate for further evaluation in major depressive disorder.