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

Published on 2018-04-13T20:08:21Z (GMT) by
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.

Cite this collection

Marcin, Lawrence R.; Warrier, Jayakumar; Thangathirupathy, Srinivasan; Shi, Jianliang; Karageorge, George N.; Pearce, Bradley C.; Ng, Alicia; Park, Hyunsoo; Kempson, James; Li, Jianqing; Zhang, Huiping; Mathur, Arvind; Reddy, Aliphedi B.; Nagaraju, G.; Tonukunuru, Gopikishan; Gupta, Grandhi V. R.

K. M.; Kamble, Manjunatha; Mannoori, Raju; Cheruku, Srinivas; Jogi, Srinivas; Gulia, Jyoti; Bastia, Tanmaya; Sanmathi, Charulatha; Aher, Jayant; Kallem, Rajareddy; Srikumar, Bettadapura N.; Vijaya, Kumar Kuchibhotla; Naidu, Pattipati S.; Paschapur, Mahesh; Kalidindi, Narasimharaju; Vikramadithyan, Reeba; Ramarao, Manjunath; Denton, Rex; Molski, Thaddeus; Shields, Eric; Subramanian, Murali; Zhuo, Xiaoliang; Nophsker, Michelle; Simmermacher, Jean; Sinz, Michael; Albright, Charlie; J. Bristow, Linda; Islam, Imadul; Bronson, Joanne J.; Olson, Richard E.; King, Dalton; Thompson, Lorin A.; Macor, John E. (2018): BMS-986163, a Negative Allosteric Modulator of GluN2B

with Potential Utility in Major Depressive Disorder. ACS Publications. Collection.