()-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (BMS-986169) and the phosphate prodrug 4-((3,4)-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 -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 (K = 4.03-6.3 nM) and selectively inhibited GluN2B receptor function in Xenopus oocytes expressing human -methyl-d-aspartate receptor subtypes (IC = 24.1 nM). BMS-986169 weakly inhibited human ether-a-go-go-related gene channel activity (IC = 28.4 M) 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[]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.

There is a significant unmet medical need for more efficacious and rapidly acting antidepressants. Toward this end, negative allosteric modulators of the -methyl-d-aspartate receptor subtype GluN2B have demonstrated encouraging therapeutic potential. We report herein the discovery and preclinical profile of a water-soluble intravenous prodrug BMS-986163 () and its active parent molecule BMS-986169 (), which demonstrated high binding affinity for the GluN2B allosteric site ( = 4.0 nM) and selective inhibition of GluN2B receptor function (IC = 24 nM) in cells. The conversion of prodrug to parent was rapid in vitro and in vivo across preclinical species. After intravenous administration, compounds and have exhibited robust levels of ex vivo GluN2B target engagement in rodents and antidepressant-like activity in mice. No significant off-target activity was observed for ,, or the major circulating metabolites and. The prodrug BMS-986163 () has demonstrated an acceptable safety and toxicology profile and was selected as a preclinical candidate for further evaluation in major depressive disorder.