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
[This corrects the article DOI: 10.1021/acsmedchemlett.7b00418.].
RESUMEN
A new series of 3,3'-spirocyclic-2-oxo-indoline derivatives was synthesized and evaluated against respiratory syncytial virus (RSV) in a cell-based assay and animal model. Extensive structure-activity relationship study led to a lead compound 14h, which exhibited excellent in vitro potency with an EC50 value of 0.8 nM and demonstrated 71% oral bioavailability in mice. In a mouse challenge model of RVS infection, 14h demonstrated superior efficacy with a 3.9log RSV virus load reduction in the lung following an oral dose of 50 mg/kg.