molecules of the month

Context. “Compound 20” (Gedeon Richter) is an oral α5-GABAA receptor negative allosteric modulator (NAM) being developed for cognitive disorders. GABA receptor NAMs are known to exert effects opposite to the anxiolytic and anticonvulsant effects of positive allosteric modulators. However, NAM agents targeting α5-GABAA receptors, which have been implicated in learning and memory, have been heavily pursued as a potential treatment for cognitive impairment. Despite promising preclinical efficacy and safety data, NAMs have continually failed in clinical development due to poor efficacy and/or tolerability. Notably, early NAM agents developed in the mid-to-late 2000s, such as Merck’s L-655,708 and α5IA (and its follow-up compound MRK-016), which was the first NAM to enter clinical development, have all failed in Ph. I/II studies. Further,…