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

Abstract In a search for GABA A 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.