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

Abstract

()-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.

BMS-986163, a Negative Allosteric Modulator of GluN2B with Potential Utility in Major Depressive Disorder

“…20 In vitro screening of BMS-986169 against a broad panel of G-protein coupled receptors (including adrenergic α1), ion channels, nuclear hormone receptors, and enzymes revealed no other significant activity. 20 BMS-986169 was negative in an exploratory AMES study. Serum protein binding of BMS- 986169 was within a 2-fold multiple across species with average free fractions between 6 and 12%.…”

“…at 73% ex vivo GluN2B receptor occupancy and an average terminal plasma concentration of 270 nM (Table 3). 20 The brain-to-plasma ratio in mice was favorable at 2.8. In context of plasma free drug concentration at the MED versus hERG IC 50 , the multiple was 875-fold.…”

“…In this Letter, we disclose medicinal chemistry efforts that culminated in the discovery of an optimized GluN2B NAM BMS-986169 (5) and its water-soluble prodrug BMS-986163 (6). 20 The ligand-based pharmacophore model for Ifenprodil-like GluN2B NAMs consists of two nonpolar aromatic rings connected by a linker that typically contains a basic nitrogen and spans 9−11 Å. 21 Guided by this model, we designed and prepared a variety of novel GluN2B NAMs with heteroatom containing linkers having nonplanar conformational restrictions that might impart superior selectivity and retain drug-like properties.…”

“…20 In addition to potent rat brain GluN2B binding, compound 5 maintained high affinity for GluN2B receptors in brain preparations from monkey and human (Table 3). 20 BMS-986169 also demonstrated potent and selective functional inhibition of GluN2B in comparison to other NMDA receptor subtypes, including GluN2A, GluN2C, GluN2D. 20 In vitro screening of BMS-986169 against a broad panel of G-protein coupled receptors (including adrenergic α1), ion channels, nuclear hormone receptors, and enzymes revealed no other significant activity.…”

“…20 BMS-986169 also demonstrated potent and selective functional inhibition of GluN2B in comparison to other NMDA receptor subtypes, including GluN2A, GluN2C, GluN2D. 20 In vitro screening of BMS-986169 against a broad panel of G-protein coupled receptors (including adrenergic α1), ion channels, nuclear hormone receptors, and enzymes revealed no other significant activity. 20 BMS-986169 was negative in an exploratory AMES study.…”