1 research outputs found
BMS-986163, a Negative Allosteric Modulator of GluN2B with Potential Utility in Major Depressive Disorder
There
is a significant unmet medical need for more efficacious
and rapidly acting antidepressants. Toward this end, negative allosteric
modulators of the <i>N</i>-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 (<b>6</b>) and its active parent
molecule BMS-986169 (<b>5</b>), which demonstrated high binding
affinity for the GluN2B allosteric site (<i>K</i><sub>i</sub> = 4.0 nM) and selective inhibition of GluN2B receptor function (IC<sub>50</sub> = 24 nM) in cells. The conversion of prodrug <b>6</b> to parent <b>5</b> was rapid in vitro and in vivo across preclinical
species. After intravenous administration, compounds <b>5</b> and <b>6</b> 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 <b>5</b>, <b>6</b>, or the major circulating metabolites <b>met-1</b> and <b>met-2</b>. The prodrug BMS-986163 (<b>6</b>)
has demonstrated an acceptable safety and toxicology profile and was
selected as a preclinical candidate for further evaluation in major
depressive disorder