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 <i>in vivo</i> active compounds. One of these compounds, <b>25</b> showed high efficacy and safety in preclinical <i>in vivo</i> models; this allowed its nomination as a novel, nonacetylenic mGluR5 NAM clinical candidate. Compound <b>25</b> was advanced to first-in-man trials for the treatment of psychiatric conditions