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J Pharmacol Exp Ther. September 27, 2017;

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 (GluN2B) Receptor Negative Allosteric Modulator with Potential in Major Depressive Disorder.

Bristow LJ , Gulia J , Weed MR , Srikumar BN , Li YW , Graef JD , Naidu PS , Sanmathi C , Aher J , Bastia T , Paschapur M , Kalidindi N , Kumar KV , Molski T , Pieschl R , Fernandes A , Brown JM , Sivarao DV , Newberry K , Bookbinder M , Polino J , Keavy D , Newton A , Shields E , Simmermacher J , Kempson J , Li J , Zhang H , Mathur A , Kallem RR , Sinha M , Ramarao M , Vikramadithyan RK , Thangathirupathy S , Warrier J , Bronson JJ , Olson RE , Macor JE , Albright CF , King D , Thompson LA , Marcin LR , Sinz M .

(R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (BMS-986169), and the phosphate prodrug (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 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 (hERG) channel activity (IC50 = 28.4 micromolar) 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]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.

PubMed ID: 28954811
Article link: J Pharmacol Exp Ther.

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