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BMS-986163, a Negative Allosteric Modulator of GluN2B with Potential Utility in Major Depressive Disorder
journal contribution
posted on 2018-04-13, 20:03 authored by 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. MacorThere
is a significant unmet medical need for more efficacious
and rapidly acting antidepressants. Toward this end, negative allosteric
modulators of the N-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 (6) and its active parent
molecule BMS-986169 (5), which demonstrated high binding
affinity for the GluN2B allosteric site (Ki = 4.0 nM) and selective inhibition of GluN2B receptor function (IC50 = 24 nM) in cells. The conversion of prodrug 6 to parent 5 was rapid in vitro and in vivo across preclinical
species. After intravenous administration, compounds 5 and 6 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 5, 6, or the major circulating metabolites met-1 and met-2. The prodrug BMS-986163 (6)
has demonstrated an acceptable safety and toxicology profile and was
selected as a preclinical candidate for further evaluation in major
depressive disorder.
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GluN 2BMajor Depressive Disordermethyl-d-aspartate receptor subtype GluN 2B24 nMoff-target activityprodrug 6vivo GluN 2B target engagementGluN 2B receptor function4.0 nMparent 5K iPotential Utilityantidepressant-like activityprodrug BMS -986163Negative Allosteric Modulatorbinding affinityGluN 2B allosteric siteallosteric modulatorsIC 50depressive disordertoxicology profileparent molecule BMS -986169compounds 5
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