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

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

  • ACS Med Chem Lett. 2018 Apr 13;9(5):472-477. doi: 10.1021/acsmedchemlett.8b00080.
Lawrence R Marcin 1 Jayakumar Warrier 2 Srinivasan Thangathirupathy 2 Jianliang Shi 3 George N Karageorge 1 Bradley C Pearce 1 Alicia Ng 1 Hyunsoo Park 3 James Kempson 3 Jianqing Li 3 Huiping Zhang 3 Arvind Mathur 3 Aliphedi B Reddy 2 G Nagaraju 2 Gopikishan Tonukunuru 2 Grandhi V R K M Gupta 2 Manjunatha Kamble 2 Raju Mannoori 2 Srinivas Cheruku 2 Srinivas Jogi 2 Jyoti Gulia 2 Tanmaya Bastia 2 Charulatha Sanmathi 2 Jayant Aher 2 Rajareddy Kallem 2 Bettadapura N Srikumar 2 Kumar Kuchibhotla Vijaya 2 Pattipati S Naidu 2 Mahesh Paschapur 2 Narasimharaju Kalidindi 2 Reeba Vikramadithyan 2 Manjunath Ramarao 2 Rex Denton 3 Thaddeus Molski 1 Eric Shields 1 Murali Subramanian 2 Xiaoliang Zhuo 1 Michelle Nophsker 1 Jean Simmermacher 1 Michael Sinz 2 Charlie Albright 1 Linda J Bristow 1 Imadul Islam 2 Joanne J Bronson 1 Richard E Olson 1 Dalton King 1 Lorin A Thompson 1 John E Macor 1
Affiliations

Affiliations

  • 1 Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
  • 2 Biocon Bristol-Myers Squibb Research Center, Bangalore, India.
  • 3 Bristol-Myers Squibb Research and Development, 3551 Lawrenceville Road, Princeton, New Jersey 08648, United States.
Abstract

There 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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