4 research outputs found
Evolution of a Scale-Up Synthesis to a Potent GluN2B Inhibitor and Its Prodrug
This paper describes the efficient
scale-up synthesis of the potent
negative allosteric glutamate N2B (GluN2B) inhibitor <b>1</b> (BMS-986169), which relies upon a stereospecific S<sub>N</sub>2
alkylation strategy and a robust process for the preparation of its
phosphate prodrug <b>28</b> (BMS-986163) from parent <b>1</b> using POCl<sub>3</sub>. A deoxyfluorination reaction employing bisÂ(2-methoxyethyl)Âaminosulfur
trifluoride (Deoxo-Fluor) is also used to stereospecifically introduce
a fluorine substituent. The optimized routes have been demonstrated
to provide APIs suitable for toxicological studies in vivo
The Discovery of GSK3640254, a Next-Generation Inhibitor of HIV‑1 Maturation
GSK3640254 is an HIV-1 maturation inhibitor (MI) that
exhibits
significantly improved antiviral activity toward a range of clinically
relevant polymorphic variants with reduced sensitivity toward the
second-generation MI GSK3532795 (BMS-955176). The key structural difference
between GSK3640254 and its predecessor is the replacement of the para-substituted benzoic acid moiety attached at the C-3
position of the triterpenoid core with a cyclohex-3-ene-1-carboxylic
acid substituted with a CH2F moiety at the carbon atom
α- to the pharmacophoric carboxylic acid. This structural element
provided a new vector with which to explore structure–activity
relationships (SARs) and led to compounds with improved polymorphic
coverage while preserving pharmacokinetic (PK) properties. The approach
to the design of GSK3640254, the development of a synthetic route
and its preclinical profile are discussed. GSK3640254 is currently
in phase IIb clinical trials after demonstrating a dose-related reduction
in HIV-1 viral load over 7–10 days of dosing to HIV-1-infected
subjects
The Discovery of GSK3640254, a Next-Generation Inhibitor of HIV‑1 Maturation
GSK3640254 is an HIV-1 maturation inhibitor (MI) that
exhibits
significantly improved antiviral activity toward a range of clinically
relevant polymorphic variants with reduced sensitivity toward the
second-generation MI GSK3532795 (BMS-955176). The key structural difference
between GSK3640254 and its predecessor is the replacement of the para-substituted benzoic acid moiety attached at the C-3
position of the triterpenoid core with a cyclohex-3-ene-1-carboxylic
acid substituted with a CH2F moiety at the carbon atom
α- to the pharmacophoric carboxylic acid. This structural element
provided a new vector with which to explore structure–activity
relationships (SARs) and led to compounds with improved polymorphic
coverage while preserving pharmacokinetic (PK) properties. The approach
to the design of GSK3640254, the development of a synthetic route
and its preclinical profile are discussed. GSK3640254 is currently
in phase IIb clinical trials after demonstrating a dose-related reduction
in HIV-1 viral load over 7–10 days of dosing to HIV-1-infected
subjects
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