Imidazo[1,5-a][1,2,4]-triazolo[1,5-d][1,4]benzodiazepines as potent and highly selective GABAA α5 inverse agonists with potential for the treatment of cognitive dysfunction

In a search for GABAA α5 ligands that combine high subtype binding selectivity with a marked inverse agonism imidazo[1,5-a][1,2,4]-triazolo[1,5-d][1,4]benzodiazepines were identified as a promising class. A short tandem reaction allowed rapid access to this chemical series, thereby facilitating rapid SAR generation which guided the optimization process. Two compounds (10e and 11f) were found to be active in an in vivo paradigm for cognitive improvement.

Graphical abstractWe have discovered a novel class of imidazo[1,5-a][1,2,4]-triazolo[1,5-d][1,4]benzodiazepines as a promising class of GABAA α5 ligands which combine both high subtype binding selectivity with a marked inverse agonism. Two compounds (10e and 11f) were found to be active in an in vivo model for cognitive improvement.Figure optionsDownload full-size imageDownload as PowerPoint slide