PT  - JOURNAL ARTICLE
AU  - Bristow, Linda J.
AU  - Gulia, Jyoti
AU  - Weed, Michael R.
AU  - Srikumar, Bettadapura N.
AU  - Li, Yu-Wen
AU  - Graef, John D.
AU  - Naidu, Pattipati S.
AU  - Sanmathi, Charulatha
AU  - Aher, Jayant
AU  - Bastia, Tanmaya
AU  - Paschapur, Mahesh
AU  - Kalidindi, Narasimharaju
AU  - Kumar, Kuchibhotla Vijaya
AU  - Molski, Thaddeus
AU  - Pieschl, Rick
AU  - Fernandes, Alda
AU  - Brown, Jeffrey M.
AU  - Sivarao, Digavalli V.
AU  - Newberry, Kimberly
AU  - Bookbinder, Mark
AU  - Polino, Joseph
AU  - Keavy, Deborah
AU  - Newton, Amy
AU  - Shields, Eric
AU  - Simmermacher, Jean
AU  - Kempson, James
AU  - Li, Jianqing
AU  - Zhang, Huiping
AU  - Mathur, Arvind
AU  - Kallem, Raja Reddy
AU  - Sinha, Meenakshee
AU  - Ramarao, Manjunath
AU  - Vikramadithyan, Reeba K.
AU  - Thangathirupathy, Srinivasan
AU  - Warrier, Jayakumar
AU  - Islam, Imadul
AU  - Bronson, Joanne J.
AU  - Olson, Richard E.
AU  - Macor, John E.
AU  - Albright, Charlie F.
AU  - King, Dalton
AU  - Thompson, Lorin A.
AU  - Marcin, Lawrence R.
AU  - Sinz, Michael
TI  - Preclinical Characterization of (<em>R</em>)-3-((3<em>S</em>,4<em>S</em>)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (BMS-986169), a Novel, Intravenous, Glutamate <em>N</em>-Methyl-<span class="sc">d</span>-Aspartate 2B Receptor Negative Allosteric Modulator with Potential in Major Depressive Disorder
AID  - 10.1124/jpet.117.242784
DP  - 2017 Dec 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 377--393
VI  - 363
IP  - 3
4099  - http://jpet.aspetjournals.org/content/363/3/377.short
4100  - http://jpet.aspetjournals.org/content/363/3/377.full
SO  - J Pharmacol Exp Ther2017 Dec 01; 363
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.