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.