Preclinical Characterization of (R)-3-((3 S,4 S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (BMS-986169), a Novel, Intravenous, Glutamate N-Methyl-d-Aspartate 2B Receptor Negative Allosteric Modulator with Potential in Major Depressive Disorder

  • J Pharmacol Exp Ther. 2017 Dec;363(3):377-393. doi: 10.1124/jpet.117.242784.
Linda J Bristow  1 ,  Jyoti Gulia  2 ,  Michael R Weed  2 ,  Bettadapura N Srikumar  2 ,  Yu-Wen Li  2 ,  John D Graef  2 ,  Pattipati S Naidu  2 ,  Charulatha Sanmathi  2 ,  Jayant Aher  2 ,  Tanmaya Bastia  2 ,  Mahesh Paschapur  2 ,  Narasimharaju Kalidindi  2 ,  Kuchibhotla Vijaya Kumar  2 ,  Thaddeus Molski  2 ,  Rick Pieschl  2 ,  Alda Fernandes  2 ,  Jeffrey M Brown  2 ,  Digavalli V Sivarao  2 ,  Kimberly Newberry  2 ,  Mark Bookbinder  2 ,  Joseph Polino  2 ,  Deborah Keavy  2 ,  Amy Newton  2 ,  Eric Shields  2 ,  Jean Simmermacher  2 ,  James Kempson  2 ,  Jianqing Li  2 ,  Huiping Zhang  2 ,  Arvind Mathur  2 ,  Raja Reddy Kallem  2 ,  Meenakshee Sinha  2 ,  Manjunath Ramarao  2 ,  Reeba K Vikramadithyan  2 ,  Srinivasan Thangathirupathy  2 ,  Jayakumar Warrier  2 ,  Imadul Islam  2 ,  Joanne J Bronson  2 ,  Richard E Olson  2 ,  John E Macor  2 ,  Charlie F Albright  2 ,  Dalton King  2 ,  Lorin A Thompson  2 ,  Lawrence R Marcin  2 ,  Michael Sinz  2
Affiliations
  • 1. Neuroscience Discovery Biology (L.J.B., M.R.W., Y.-W.L., J.D.G., T.M., R.P., A.F., J.M.B., D.V.S., K.N., M.B., J.P., D.K., A.N., C.F.A.), Neuroscience Discovery Chemistry (J.J.B., R.E.O., J.E.M., D.K., L.A.T., L.R.M.), and Preclinical Candidate Optimization (E.S., J.S., Mi.S.), Bristol-Myers Squibb Company, Wallingford, Connecticut; Discovery Synthesis, Bristol-Myers Squibb Company, Lawrenceville, Princeton, New Jersey (J.K., J.L., H.Z., A.M.); and Biocon Bristol-Myers Squibb Research Center, Bangalore, India (J.G., B.N.S., P.S.N., C.S., J.A., T.B., M.P., N.K., K.V.K., R.R.K., Me.S., M.R., R.K.V., S.T., J.W. I.I.) [email protected] [email protected].
  • 2. Neuroscience Discovery Biology (L.J.B., M.R.W., Y.-W.L., J.D.G., T.M., R.P., A.F., J.M.B., D.V.S., K.N., M.B., J.P., D.K., A.N., C.F.A.), Neuroscience Discovery Chemistry (J.J.B., R.E.O., J.E.M., D.K., L.A.T., L.R.M.), and Preclinical Candidate Optimization (E.S., J.S., Mi.S.), Bristol-Myers Squibb Company, Wallingford, Connecticut; Discovery Synthesis, Bristol-Myers Squibb Company, Lawrenceville, Princeton, New Jersey (J.K., J.L., H.Z., A.M.); and Biocon Bristol-Myers Squibb Research Center, Bangalore, India (J.G., B.N.S., P.S.N., C.S., J.A., T.B., M.P., N.K., K.V.K., R.R.K., Me.S., M.R., R.K.V., S.T., J.W. I.I.).
PMID: 28954811 DOI: 10.1124/jpet.117.242784
Abstract

(R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (BMS-986169) and the phosphate prodrug 4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl dihydrogen phosphate (BMS-986163) were identified from a drug discovery effort focused on the development of novel, intravenous glutamate N-methyl-d-aspartate 2B receptor (GluN2B) negative allosteric modulators (NAMs) for treatment-resistant depression (TRD). BMS-986169 showed high binding affinity for the GluN2B subunit allosteric modulatory site (Ki = 4.03-6.3 nM) and selectively inhibited GluN2B receptor function in Xenopus oocytes expressing human N-methyl-d-aspartate receptor subtypes (IC50 = 24.1 nM). BMS-986169 weakly inhibited human ether-a-go-go-related gene channel activity (IC50 = 28.4 μM) and had negligible activity in an assay panel containing 40 additional pharmacological targets. Intravenous administration of BMS-986169 or BMS-986163 dose-dependently increased GluN2B receptor occupancy and inhibited in vivo [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine ([3H]MK-801) binding, confirming target engagement and effective cleavage of the prodrug. BMS-986169 reduced immobility in the mouse forced swim test, an effect similar to intravenous ketamine treatment. Decreased novelty suppressed feeding latency, and increased ex vivo hippocampal long-term potentiation was also seen 24 hours after acute BMS-986163 or BMS-986169 administration. BMS-986169 did not produce ketamine-like hyperlocomotion or abnormal behaviors in mice or cynomolgus monkeys but did produce a transient working memory impairment in monkeys that was closely related to plasma exposure. Finally, BMS-986163 produced robust changes in the quantitative electroencephalogram power band distribution, a translational measure that can be used to assess pharmacodynamic activity in healthy humans. Due to the poor aqueous solubility of BMS-986169, BMS-986163 was selected as the lead GluN2B NAM candidate for further evaluation as a novel intravenous agent for TRD.

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