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

Abstract

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.

Copper‐Catalyzed Electrophilic Cyclization of N‐Propargylamines with Sodium Sulfinate for the Synthesis of 3‐Sulfonated Quinolines

“…To our delight, the aliphatic sodium sulfinates including sodium methanesulfinates and sodium ethanesulfinates were also tolerated, giving the corresponding products 32 and 33 in 63 % and 55 % yields, respectively. In addition, the analogue 34 of drug candidate RGH‐618 could be easily synthesized through this copper‐catalyzed electrophilic cyclization.…”

Allosteric Molecular Switches in Metabotropic Glutamate Receptors

“…As these effects are hardly predictable and the properties of allosteric sites are often challenged the ADME properties of the ligands, multidimensional parallel optimization strategies are typically considered [138] . The implementation of this iterative, multidimensional parallel synthesis strategy has been recently exemplified by the optimization of an mGlu5 NAM to clinical candidate [139] . The procedure starts with the retrosynthetic deconvolution of the starting point to identify regions to be optimized (Figure 4).…”

Visible‐light‐mediated Synthesis of 3‐Sulfonylquinolines: Mechanistic Insights into the Photoredox Catalysis

“…[6,7] Again, compounds 2 and 3 (RGH-618 and mGluR5, respectively) have been proposed as negative allosteric inhibitors of negative allosteric modulators of GluR5 receptors and are being clinically developed for the treatment of hypertensions and psychiatric conditions. [8,9] A few recent methods for the synthesis of 3-sulfonylquinolines have been reported (Scheme 1). Most of these methods have focused on the concommitant introduction of the arylsulfonyl group and the quinoline ring formation using Npropargylanilines.…”