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J Med Chem ; 67(1): 728-753, 2024 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-38156615

RESUMO

Alcohol use disorder (AUD) results in numerous disabilities and approximately 3 million deaths annually, caused mainly by alcoholic liver disease (ALD). Phosphodiesterase IV (PDE4) has emerged as an attractive molecular target for a new treatment for AUD and ALD. In this study, we describe the identification of 5-azaindazole analogues as PDE4 inhibitors against AUD and ALD. System optimization studies led to the discovery of ZL40 (IC50 = 37.4 nM) with a remarkable oral bioavailability (F = 94%), satisfactory safety, and a lower emetogenic potency than the approved PDE4 inhibitors roflumilast and apremilast. Encouragingly, ZL40 exhibited AUD therapeutic effects by decreasing alcohol intake and improving acute alcohol-induced sedation and motor impairment. Meanwhile, ZL40 displayed the potential to alleviate alcoholic liver injury and attenuate inflammation in the NIAAA mice model. These results showed that ZL40 is a promising compound for future drug development to treat alcohol-related diseases.


Assuntos
Alcoolismo , Hepatopatias Alcoólicas , Inibidores da Fosfodiesterase 4 , Camundongos , Animais , Inibidores da Fosfodiesterase 4/farmacologia , Inibidores da Fosfodiesterase 4/uso terapêutico , Alcoolismo/tratamento farmacológico , Hepatopatias Alcoólicas/tratamento farmacológico , Etanol/uso terapêutico , Consumo de Bebidas Alcoólicas
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