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

Abstract

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.

Synthesis and Preliminary Evaluations of a Triazole-Cored Antagonist as a PET Imaging Probe ([18F]N2B-0518) for GluN2B Subunit in the Brain

“…The nonspecific binding was determined by self-blocking studies using non-radioactive 13 (10 μM, Figure 5B) and the results showed that the radioactivity of [ 18 F]13 distributed to several brain regions with high specificity including hippocampus (87%, n = 3, p <0.001, T-test, Figure 5D), entorhinal cortex (89%, p <0.01), insular cortex (82%, p <0.001), caudate nucleus (79%, p <0.01), and putamen (73%, p <0.01), but lower in thalamus (53%, p <0.01). The specific binding to NMDAR GluN2B subtype was further confirmed by the blocking experiments with BMT-108908 (10 μM) 60,61 and the %blockade results were similar to those of self-blocking studies (Figure 5C and 5D). In summary, [ 18 F]13 showed high specific binding to GluN2B subunit in the NHP brain sections, which showed characteristic and regional-specific GluN2B subunit expression and target specificity (validated by blocking studies).…”

Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels

“…101,606 (Chenard et al, 1995), radiprodil (Mullier et al, 2017), Merck-20j, andMK-0657 (Liverton et al, 2007;Addy et al, 2009) (Table 10). Alternative scaffolds include propanolamines (Tahirovic et al, 2008), benzimidazoles (McCauley et al, 2004;Davies et al, 2012), cyclic benzamidines (Nguyen et al, 2007), amino cyclopentanes (Layton et al, 2011), piperidinyl pyrrolidinones (Marcin et al, 2018), and other compounds (Claiborne et al, 2003;McIntyre et al, 2009;Mosley et al, 2009;Brown et al, 2011;Beinat et al, 2014;Buemi et al, 2014;Bristow et al, 2017;Dey et al, 2018;Thum et al, 2018;Zscherp et al, 2018;Zampieri et al, 2019;Zhang et al, 2019). Molecules with two aromatic rings separated by a linker also cross over to act selectively on GluN2B, including the dopamine receptor antagonist haloperidol, the r and dopamine receptor antagonist trifluperidol, the H 3 histamine receptor antagonists clobenpropit and iodophenpropit, the b-adrenergic receptor agonist nylidrin, and the TRPV1 receptor antagonist capsazepine (Supplemental Table 13).…”

A Glutamate N-Methyl-d-Aspartate (NMDA) Receptor Subunit 2B–Selective Inhibitor of NMDA Receptor Function with Enhanced Potency at Acidic pH and Oral Bioavailability for Clinical Use

“…Since the discovery of GluN2B-selective antagonists, numerous scaffolds of highly selective GluN2B NMDA receptor antagonists have been reported (reviewed by Layton et al, 2006;Mony et al, 2009;Koller and Urwyler, 2010;Ruppa et al, 2012). These include phenethanolamines such as ifenprodil (Williams, 1993), eliprodil (Carter et al, 1988), radiprodil (Michel et al, 2014;Auvin et al, 2020), traxoprodil (Chenard et al, 1995), Ro 25-6981 (Fischer et al, 1997), MK-0657 (Addy et al, 2009), plus additional scaffolds including propanolamines (Yuan et al, 2015), benzimidazoles (McCauley et al, 2004;Davies et al, 2012), cyclic benzamidines (Nguyen et al, 2007), amino cyclopentanes (Layton et al, 2011), piperidinyl pyrrolidinones (Marcin et al, 2018), and other compounds (Mosley et al, 2009;McIntyre et al, 2009;Brown et al, 2011;Buemi et al, 2014;Dey et al, 2018;Thum et al, 2018). Whereas crystallographic evaluation of ifenprodil at the GluN1/GluN2B heterodimer amino terminal domain (ATD) interface (Karakas et al, 2014) is the likely pose for many GluN2B-selective inhibitors, recent structural data revealed a unique region within the binding cavity that can be occupied by compounds with a more compact scaffold (Kemp and Tasker, 2009;Stroebel et al, 2016).…”