RESUMO
Through iterative design cycles we have discovered a number of novel new classes where the imidazo[1,5-a][1,2,4]-triazolo[1,5-d][1,4]benzodiazepine was deemed the most promising GABA(A) alpha5 inverse agonist class with potential for cognitive enhancement. This class combines a modest subtype binding selectivity with inverse agonism and has the most favourable molecular properties for further lead optimisation towards a central nervous system (CNS) acting medicine.
Assuntos
Benzodiazepinas/química , Nootrópicos/química , Receptores de GABA-A/metabolismo , Triazóis/química , Animais , Benzodiazepinas/síntese química , Benzodiazepinas/farmacologia , Descoberta de Drogas , Agonismo Inverso de Drogas , Agonistas de Receptores de GABA-A , Humanos , Nootrópicos/síntese química , Nootrópicos/farmacologia , Oócitos/efeitos dos fármacos , Triazóis/síntese química , Triazóis/farmacologia , Xenopus laevisRESUMO
Lead optimisation of the imidazo[1,5-a][1,2,4]-triazolo[1,5-d][1,4]benzodiazepine class led to the identification of two clinical leads [RO4882224 (11) and RO4938581 (44)] functioning as novel potent and selective GABAA alpha5 inverse agonists. The unique pharmacological profiles and optimal pharmacokinetic profiles resulted in in vivo activity in selected cognition models.