BMS-986163, a Negative Allosteric Modulator of GluN2B
with Potential Utility in Major Depressive Disorder
Lawrence R. Marcin
Jayakumar Warrier
Srinivasan Thangathirupathy
Jianliang Shi
George N. Karageorge
Bradley C. Pearce
Alicia Ng
Hyunsoo Park
James Kempson
Jianqing Li
Huiping Zhang
Arvind Mathur
Aliphedi B. Reddy
G. Nagaraju
Gopikishan Tonukunuru
Grandhi V. R.
K. M. Gupta
Manjunatha Kamble
Raju Mannoori
Srinivas Cheruku
Srinivas Jogi
Jyoti Gulia
Tanmaya Bastia
Charulatha Sanmathi
Jayant Aher
Rajareddy Kallem
Bettadapura N. Srikumar
Kumar Kuchibhotla Vijaya
Pattipati S. Naidu
Mahesh Paschapur
Narasimharaju Kalidindi
Reeba Vikramadithyan
Manjunath Ramarao
Rex Denton
Thaddeus Molski
Eric Shields
Murali Subramanian
Xiaoliang Zhuo
Michelle Nophsker
Jean Simmermacher
Michael Sinz
Charlie Albright
Linda J. Bristow
Imadul Islam
Joanne J. Bronson
Richard E. Olson
Dalton King
Lorin A. Thompson
John E. Macor
10.1021/acsmedchemlett.8b00080.s001
https://acs.figshare.com/articles/journal_contribution/BMS-986163_a_Negative_Allosteric_Modulator_of_GluN2B_with_Potential_Utility_in_Major_Depressive_Disorder/6141602
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.
2018-04-13 20:03:43
GluN 2B
Major Depressive Disorder
methyl-d-aspartate receptor subtype GluN 2B
24 nM
off-target activity
prodrug 6
vivo GluN 2B target engagement
GluN 2B receptor function
4.0 nM
parent 5
K i
Potential Utility
antidepressant-like activity
prodrug BMS -986163
Negative Allosteric Modulator
binding affinity
GluN 2B allosteric site
allosteric modulators
IC 50
depressive disorder
toxicology profile
parent molecule BMS -986169
compounds 5