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 AlcoólicasRESUMO
Sepsis can quickly result in fatality for critically ill individuals, while liver damage can expedite the progression of sepsis, necessitating the exploration of new strategies for treating hepatic sepsis. PDE4 has been identified as a potential target for the treatment of liver damage. The scaffold hopping of lead compounds FCPR16 and Z19153 led to the discovery of a novel 7-methoxybenzofuran PDE4 inhibitor 4e, demonstrating better PDE4B (IC50 = 10.0 nM) and PDE4D (IC50 = 15.2 nM) inhibitor activity as a potential anti-hepatic sepsis drug in this study. Compared with FCPR16 and Z19153, 4e displayed improved oral bioavailability (F = 66 %) and longer half-life (t1/2 = 2.0 h) in SD rats, which means it can be more easily administered and has a longer-lasting effect. In the D-GalN/LPS-induced liver injury model, 4e exhibited excellent hepatoprotective activity against hepatic sepsis by decreasing ALT and AST levels and inflammatory infiltrating areas.
Assuntos
Benzofuranos , Galactosamina , Inibidores da Fosfodiesterase 4 , Sepse , Animais , Humanos , Masculino , Ratos , Benzofuranos/farmacologia , Benzofuranos/química , Benzofuranos/síntese química , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Relação Dose-Resposta a Droga , Descoberta de Drogas , Galactosamina/farmacologia , Lipopolissacarídeos/farmacologia , Lipopolissacarídeos/antagonistas & inibidores , Fígado/efeitos dos fármacos , Fígado/patologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores da Fosfodiesterase 4/farmacologia , Inibidores da Fosfodiesterase 4/química , Inibidores da Fosfodiesterase 4/síntese química , Substâncias Protetoras/farmacologia , Substâncias Protetoras/química , Substâncias Protetoras/síntese química , Ratos Sprague-Dawley , Sepse/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
Inflammatory bowel disease (IBD) is a chronic and progressive condition with a significant global burden. Currently, available treatments primarily provide symptomatic relief and retard disease progression, yet they do not offer a cure and are frequently associated with adverse effects. Therefore, the discovery of new targets and therapeutic drugs for IBD is crucial. Phosphodiesterase 4 (PDE4) inhibitors have emerged as promising candidates in the search for effective IBD treatments, although dose-dependent side effects hamper their clinical utility. In this study, building upon heterocyclic biaryl derivatives (TPA16), we designed and synthesized a series of N2-substituted indazole-based PDE4D inhibitors, emphasizing improving safety profiles. An enzyme activity screening discovered an optimized compound, LZ-14 (Z21115), which exhibited high PDE4D7 (IC50 = 10.5 nM) inhibitory activity and good selectivity. More interestingly, LZ-14 has demonstrated promising effects in treating IBD in mouse models by improving the inflammatory response and colon injury. Furthermore, LZ-14 displayed low emetogenic potential in ketamine/xylazine anesthesia mice alternative models.