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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