RESUMO
Recently, we identified a novel phosphodiesterase 2A (PDE2A) inhibitor, PDM-631 ((S)-3-cyclopropyl-6-methyl-1-(1-(4-(trifluoromethoxy)phenyl)propan-2-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one). PDM-631 showed potent inhibitory activities for human and rat PDE2A with IC50 values of 1.5 and 4.2nM, respectively and more than 2000-fold selectivity against other phosphodiesterases. In rat studies, PDM-631 showed oral bioavailability and good brain penetration, and increased the cGMP levels in the cortex. These data indicate that PDM-631 is a potent, selective, orally active, and brain-penetrable PDE2A inhibitor. In behavioral studies using rat models, PDM-631 (3-30mg/kg) resulted in better discrimination between a novel object and a familiar one 48h after the acquisition phase in the novel object recognition test, thus indicating that PDM-631 increased object recognition memory. In contrast, PDM-631 did not attenuate the conditioned avoidance response at the same dose range (3-30mg/kg) in rats, indicating that PDM-631 did not show an antipsychotic-like effect. In test for extrapyramidal side effect, PDM-631 had no effect on catalepsy at the effective doses (10 and 30mg/kg) in the novel object recognition test, while haloperidol caused catalepsy at a dose of 3mg/kg. Our results suggest that PDM-631 is a good pharmacological tool that can be used to investigate the role of PDE2A and may have therapeutic potential for the treatment of cognitive impairments associated with schizophrenia and neurodegenerative disorders, without any extrapyramidal side effects.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/antagonistas & inibidores , Pirazóis/administração & dosagem , Pirazóis/farmacologia , Administração Oral , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Condicionamento Psicológico/efeitos dos fármacos , GMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/metabolismo , Relação Dose-Resposta a Droga , Desenho de Fármacos , Masculino , Pirazóis/farmacocinética , Pirimidinas , Ratos , Ratos Sprague-Dawley , Reconhecimento Psicológico/efeitos dos fármacosRESUMO
Using structure based drug design, novel aminobenzisoxazoles as coagulation factor IXa inhibitors were designed and synthesized. Highly selective inhibition of FIXa over FXa was demonstrated. Anticoagulation profile of selected compounds was evaluated by aPTT and PT tests. In vitro ADMET and pharmacokinetic (PK) profiles were also evaluated.