RT Journal Article SR Electronic T1 Preclinical Characterization of (R)-3-((3S,4S)-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 JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 377 OP 393 DO 10.1124/jpet.117.242784 VO 363 IS 3 A1 Linda J. Bristow A1 Jyoti Gulia A1 Michael R. Weed A1 Bettadapura N. Srikumar A1 Yu-Wen Li A1 John D. Graef A1 Pattipati S. Naidu A1 Charulatha Sanmathi A1 Jayant Aher A1 Tanmaya Bastia A1 Mahesh Paschapur A1 Narasimharaju Kalidindi A1 Kuchibhotla Vijaya Kumar A1 Thaddeus Molski A1 Rick Pieschl A1 Alda Fernandes A1 Jeffrey M. Brown A1 Digavalli V. Sivarao A1 Kimberly Newberry A1 Mark Bookbinder A1 Joseph Polino A1 Deborah Keavy A1 Amy Newton A1 Eric Shields A1 Jean Simmermacher A1 James Kempson A1 Jianqing Li A1 Huiping Zhang A1 Arvind Mathur A1 Raja Reddy Kallem A1 Meenakshee Sinha A1 Manjunath Ramarao A1 Reeba K. Vikramadithyan A1 Srinivasan Thangathirupathy A1 Jayakumar Warrier A1 Imadul Islam A1 Joanne J. Bronson A1 Richard E. Olson A1 John E. Macor A1 Charlie F. Albright A1 Dalton King A1 Lorin A. Thompson A1 Lawrence R. Marcin A1 Michael Sinz YR 2017 UL http://jpet.aspetjournals.org/content/363/3/377.abstract AB (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.