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
  • 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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