BMS-986163, a Negative Allosteric Modulator of GluN2B with Potential Utility in Major Depressive Disorder Lawrence R. Marcin Jayakumar Warrier Srinivasan Thangathirupathy Jianliang Shi George N. Karageorge Bradley C. Pearce Alicia Ng Hyunsoo Park James Kempson Jianqing Li Huiping Zhang Arvind Mathur Aliphedi B. Reddy G. Nagaraju Gopikishan Tonukunuru Grandhi V. R. K. M. Gupta Manjunatha Kamble Raju Mannoori Srinivas Cheruku Srinivas Jogi Jyoti Gulia Tanmaya Bastia Charulatha Sanmathi Jayant Aher Rajareddy Kallem Bettadapura N. Srikumar Kumar Kuchibhotla Vijaya Pattipati S. Naidu Mahesh Paschapur Narasimharaju Kalidindi Reeba Vikramadithyan Manjunath Ramarao Rex Denton Thaddeus Molski Eric Shields Murali Subramanian Xiaoliang Zhuo Michelle Nophsker Jean Simmermacher Michael Sinz Charlie Albright Linda J. Bristow Imadul Islam Joanne J. Bronson Richard E. Olson Dalton King Lorin A. Thompson John E. Macor 10.1021/acsmedchemlett.8b00080.s001 https://acs.figshare.com/articles/journal_contribution/BMS-986163_a_Negative_Allosteric_Modulator_of_GluN2B_with_Potential_Utility_in_Major_Depressive_Disorder/6141602 There is a significant unmet medical need for more efficacious and rapidly acting antidepressants. Toward this end, negative allosteric modulators of the <i>N</i>-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 (<b>6</b>) and its active parent molecule BMS-986169 (<b>5</b>), which demonstrated high binding affinity for the GluN2B allosteric site (<i>K</i><sub>i</sub> = 4.0 nM) and selective inhibition of GluN2B receptor function (IC<sub>50</sub> = 24 nM) in cells. The conversion of prodrug <b>6</b> to parent <b>5</b> was rapid in vitro and in vivo across preclinical species. After intravenous administration, compounds <b>5</b> and <b>6</b> 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 <b>5</b>, <b>6</b>, or the major circulating metabolites <b>met-1</b> and <b>met-2</b>. The prodrug BMS-986163 (<b>6</b>) has demonstrated an acceptable safety and toxicology profile and was selected as a preclinical candidate for further evaluation in major depressive disorder. 2018-04-13 20:03:43 GluN 2B Major Depressive Disorder methyl-d-aspartate receptor subtype GluN 2B 24 nM off-target activity prodrug 6 vivo GluN 2B target engagement GluN 2B receptor function 4.0 nM parent 5 K i Potential Utility antidepressant-like activity prodrug BMS -986163 Negative Allosteric Modulator binding affinity GluN 2B allosteric site allosteric modulators IC 50 depressive disorder toxicology profile parent molecule BMS -986169 compounds 5