Discovery and Preclinical Characterization of 3‑((4-(4-Chlorophenyl)-7-fluoroquinoline-3-yl)sulfonyl)benzonitrile, a Novel Non-acetylenic Metabotropic Glutamate Receptor 5 (mGluR5) Negative Allosteric Modulator for Psychiatric Indications

Negative allosteric modulators (NAM)
of metabotropic glutamate
receptor 5 (mGluR5) have been implicated as a potential pharmacotherapy
for a number of psychiatric diseases, including anxiety and depression.
Most of the mGluR5 NAM clinical candidates can be characterized by
the central acetylenic moiety that connects the terminal pharmacophores.
Identification of a sulfoquinoline hit via high throughput screening
(HTS) followed by optimization provided a 4-phenyl-3-aryl-sulfoquinoline
lead compound with the minimal pharmacophore. Optimization of the
core and aryl appendages was performed by scanning and matrix libraries
synthesized by the multiple parallel synthesis approach. Biological
evaluation of matrix libraries provided a number of potent, metabolically
stable, and in vivo active compounds. One of these
compounds, 25 showed high efficacy and safety in preclinical in vivo models; this allowed its nomination as a novel,
nonacetylenic mGluR5 NAM clinical candidate. Compound 25 was advanced to first-in-man trials for the treatment of psychiatric
conditions.