RESUMEN
A series of caspase inhibitors containing γ-amino acid moiety have been synthesized. A systemic study on their structure-activity relationship of anti-apoptotic cellular activity is presented. These efforts led to the discovery of compound 20o as a potent caspase inhibitor, which demonstrated preclinical ameliorating total bilirubin efficacy with a significantly improved pharmacokinetic profile.
Asunto(s)
Aminoácidos/química , Inhibidores de Caspasas/química , Animales , Bilirrubina/sangre , Sitios de Unión , Caspasa 1/química , Caspasa 1/metabolismo , Inhibidores de Caspasas/farmacocinética , Inhibidores de Caspasas/uso terapéutico , Modelos Animales de Enfermedad , Semivida , Humanos , Células Jurkat , Hepatopatías/tratamiento farmacológico , Hepatopatías/patología , Ratones , Simulación del Acoplamiento Molecular , Estructura Terciaria de Proteína , Relación Estructura-Actividad , Receptor fas/antagonistas & inhibidores , Receptor fas/metabolismoRESUMEN
A series of octahydropyrrolo[3,4-c]pyrroles were synthesized and evaluated by orexin 1 and 2 receptor (OX1 & 2 R) antagonists assays. Compound 14l with potent OXR antagonist activity and suitable pharmacokinetic behavior was chosen to be investigated in an EEG study, which demonstrated effects of sleep promotion comparable to Suvorexant. Furthermore, the di-fluro substituted analogs exhibited reduced hERG inhibition while maintaining moderate potency.