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