2. Academic Validation
  3. 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.
PMID: 29795762 DOI: 10.1021/acsmedchemlett.8b00080
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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