RESUMO
We synthesized several biaryl derivatives as PDE10A inhibitors to prevent phototoxicity of 2-[4-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]oxy}methyl)phenyl]quinoline (1) and found that the energy difference between the energy-minimized conformation and the coplanar conformation of the biaryl moiety helped facilitate prediction of the phototoxic potential of biaryl compounds. Replacement of the quinoline ring of 1 with N-methyl benzimidazole increased this energy difference and prevented phototoxicity in the 3T3 NRU test. Further optimization identified 1-methyl-5-(1-methyl-3-{[4-(1-methyl-1H-benzimidazol-4-yl)phenoxy]methyl}-1H-pyrazol-4-yl)pyridin-2(1H)-one (38b). Compound 38b exhibited good selectivity against other PDEs, and oral administration of 38b improved visual-recognition memory deficit in mice at doses of 0.001 and 0.003mg/kg in the novel object recognition test. ASP9436 (sesquiphosphate of 38b) may therefore be used for the treatment of schizophrenia with a low risk of phototoxicity.
Assuntos
Antipsicóticos/química , Benzimidazóis/química , Inibidores de Fosfodiesterase/química , Diester Fosfórico Hidrolases/metabolismo , Piridinas/química , Quinolinas/química , Esquizofrenia/tratamento farmacológico , Administração Oral , Animais , Antipsicóticos/administração & dosagem , Antipsicóticos/efeitos adversos , Comportamento Animal/efeitos dos fármacos , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Sítios de Ligação , Cristalografia por Raios X , Modelos Animais de Doenças , Alucinógenos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Reconhecimento Visual de Modelos/efeitos dos fármacos , Fenciclidina , Inibidores de Fosfodiesterase/administração & dosagem , Inibidores de Fosfodiesterase/efeitos adversos , Diester Fosfórico Hidrolases/química , Processos Fotoquímicos , Ligação Proteica , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Quinolinas/administração & dosagem , Quinolinas/efeitos adversos , Esquizofrenia/induzido quimicamente , Esquizofrenia/enzimologia , Esquizofrenia/fisiopatologia , Raios UltravioletaRESUMO
A novel class of phosphodiesterase 10A inhibitors with potent PDE10A inhibitory activity and reduced CYP3A4 inhibition was designed and synthesized starting from 2-[4-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]oxy}methyl)phenyl]quinoline (1). Replacement of pyridine ring of 1 with N-methyl pyridone ring drastically improved CYP3A4 inhibition, and further optimization of these quinoline analogues identified 1-methyl-5-(1-methyl-3-{[4-(quinolin-2-yl)phenoxy]methyl}-1H-pyrazol-4-yl)pyridin-2(1H)-one (42b), which showed potent PDE10A inhibitory activity and a good CYP3A4 inhibition profile. A PET study with (11)C-labeled 42b indicated that 42b exhibited good brain penetration and specifically accumulated in the rodent striatum. Further, oral administration of 42b dose-dependently attenuated phencyclidine-induced hyperlocomotion in mice with an ED50 value of 2.0mg/kg and improved visual-recognition memory impairment at 0.1 and 0.3mg/kg in mice novel object recognition test.
