A high throughput luminescent assay based on the Kinase-Glo() system (Promega, Madison, WI) has been developed for screening against glycogen synthase kinase-3beta (GSK-3beta). Careful optimization of assay parameters allowed us to develop a robust, reproducible, and sensitive assay. Its usefulness has been demonstrated in a high throughput screening run when screening 55,000 compounds. This campaign yielded five chemical classes of hits, including several highly potent GSK-3beta inhibitors.

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.

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