RESUMO
To identify phosphodiesterase-9 (PDE9) as a novel target for the treatment of vascular dementia (VaD), a series of pyrazolopyrimidinone analogues were discovered based on a hit 1. Hit-to-lead optimization resulted in a potent inhibitor 2 with excellent selectivity and physicochemical properties to enable in vivo studies. Oral administration of 2 (5.0 mg/kg) caused notable therapeutic effects in the VaD mouse model, providing a promising lead or chemical probe for investigating the biological functions of PDE9 inhibition.
Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Desenho de Fármacos , Inibidores de Fosfodiesterase/química , 3',5'-AMP Cíclico Fosfodiesterases/metabolismo , Administração Oral , Animais , Sítios de Ligação , Domínio Catalítico , Demência Vascular/tratamento farmacológico , Demência Vascular/patologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Simulação de Acoplamento Molecular , Inibidores de Fosfodiesterase/farmacologia , Inibidores de Fosfodiesterase/uso terapêutico , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Pirazóis/química , Pirazóis/metabolismo , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Piridinas/química , Piridinas/metabolismo , Piridinas/farmacologia , Piridinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Discovery of multitarget-directed ligands (MTDLs), targeting different factors simultaneously to control the complicated pathogenesis of Alzheimer's disease (AD), has become an important research area in recent years. Both phosphodiesterase 9A (PDE9A) and butyrylcholinesterase (BuChE) inhibitors could participate in different processes of AD to attenuate neuronal injuries and improve cognitive impairments. However, research on MTDLs combining the inhibition of PDE9A and BuChE simultaneously has not been reported yet. In this study, a series of novel pyrazolopyrimidinone-rivastigmine hybrids were designed, synthesized, and evaluated in vitro. Most compounds exhibited remarkable inhibitory activities against both PDE9A and BuChE. Compounds 6c and 6f showed the best IC50 values against PDE9A (6c, 14 nM; 6f, 17 nM) together with the considerable inhibition against BuChE (IC50, 6c, 3.3 µM; 6f, 0.97 µM). Their inhibitory potencies against BuChE were even higher than the anti-AD drug rivastigmine. It is worthy mentioning that both showed moderate selectivity for BuChE over acetylcholinesterase (AChE). Molecular docking studies revealed their binding patterns and explained the influence of configuration and substitutions on the inhibition of PDE9A and BuChE. Furthermore, compounds 6c and 6f exhibited negligible toxicity, which made them suitable for the further study of AD in vivo.