Identification of Triazolopyridines as Selective α5-GABA A Receptor Negative Allosteric Modulators by a Hybridization Approach

The identification and characterization of novel triazolopyridine derivatives with selective α5 subunit-containing GABA A receptor negative allosteric modulator (NAM) activity are disclosed. As a result of in silico screening of our corporate compound deck, we identified a moderately potent hit that was converted to an advanced hit bearing better physicochemical and pharmacological properties using a hybridization approach. Subsequent optimization led to the identification of in vitro potent and subtype-selective α5-GABA A receptor NAMs representing a new chemotype in this area.