RESUMO
The design, synthesis and structure activity relationship studies of a series of compounds from benzo[d]imidazo[5,1-b]thiazole scaffold as phosphodiesterase 10A (PDE10A) inhibitors are discussed. Several potent analogs with heteroaromatic substitutions (9a-d) were identified. The anticipated binding mode of these analogs was confirmed by performing the in silico docking experiments. Later, the heteroaromatics were substituted with saturated heteroalkyl groups which provided a tool compound 9e with excellent PDE10A activity, PDE selectivity, CNS penetrability and with favorable pharmacokinetic profile in rats. Furthermore, the compound 9e was shown to be efficacious in the MK-801 induced psychosis model and in the CAR model of psychosis.
Assuntos
Imidazóis/química , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/química , Tiazóis/química , Animais , Antipsicóticos/química , Antipsicóticos/farmacocinética , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Modelos Animais de Doenças , Maleato de Dizocilpina/toxicidade , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Feminino , Meia-Vida , Simulação de Acoplamento Molecular , Inibidores de Fosfodiesterase/farmacocinética , Inibidores de Fosfodiesterase/uso terapêutico , Diester Fosfórico Hidrolases/metabolismo , Transtornos Psicóticos/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Tiazóis/farmacocinética , Tiazóis/uso terapêuticoRESUMO
The synthesis and structure-activity relationship studies of a series of compounds from imidazopyridazinone scaffold as PDE7 inhibitors are disclosed. Potent analogs such as compounds 7 (31nM), 8 (27nM), and 9 (12nM) were identified. The PDE selectivity and pharmacokinetic profile of compounds 7, 8 and 9 are also disclosed. The adequate CNS penetration of compound 7 in mice allowed it to be tested in the MPTP induced PD model and haloperidol induced catalepsy model to probe the differential pharmacology of PDE7 in the striatal pathway.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 7/antagonistas & inibidores , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Imidazóis/farmacologia , Doença de Parkinson/tratamento farmacológico , Piridonas/farmacologia , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 7/metabolismo , Relação Dose-Resposta a Droga , Estabilidade de Medicamentos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Humanos , Imidazóis/química , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Doença de Parkinson/enzimologia , Doença de Parkinson/metabolismo , Piridonas/química , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/metabolismo , Relação Estrutura-AtividadeRESUMO
The synthesis and structure-activity relationship studies of isothiazole and isoxazole fused pyrimidones as PDE7 inhibitors are discussed. The pharmacokinetic profile of 10 and 21 with adequate CNS penetration, required for in vivo Parkinson's disease models, are disclosed.
