RESUMEN
Hedgehog signaling pathway inhibitors are emerging as new therapeutic intervention against cancer. A novel series of N-(2-pyrimidinylamino) benzamide derivatives as hedgehog signaling pathway inhibitors were designed and synthesized. Most compounds presented significant inhibitory effect on hedgehog signaling pathway, among which 21 compounds exhibited more potent than vismodegib. Furthermore, compound 6a showed moderate pharmacokinetic properties in vivo, representing a promising lead compound for further exploration.
Asunto(s)
Benzamidas/química , Benzamidas/farmacología , Proteínas Hedgehog/metabolismo , Pirimidinas/química , Pirimidinas/farmacología , Transducción de Señal/efectos de los fármacos , Animales , Benzamidas/síntesis química , Benzamidas/farmacocinética , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Semivida , Proteínas Hedgehog/antagonistas & inhibidores , Pirimidinas/síntesis química , Pirimidinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Fifteen PEG-scutellarin prodrugs were synthesized by modifying carboxyl and phenolic hydroxyl groups of scutellarin with mPEG of different molecular weight (400-3000). The water solubility of prodrugs increased remarkably and reached the maximum value of 783.88 mg/mL (scutellarin, 0.02 mg/mL). The anti-infarct effects of four PEG prodrugs with high water solubility were evaluated by Cerebral Ischemia/Reperfusion in the Middle Cerebral Artery Occlusion (MCAO) model. The results showed that the prodrug 7e could significantly reduce the infarct area from 27.2% to 12.2% (33.3% for the control) and decrease the neurological deficit score from 2.77 to 1.32 (2.85 for the control). The half-life (18.62 min) of the prodrug 7e was significantly longer than that of scutellarin (3.03 min).