ABSTRACT
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.
Subject(s)
Amino Acids/chemistry , Caspase Inhibitors/chemistry , Animals , Bilirubin/blood , Binding Sites , Caspase 1/chemistry , Caspase 1/metabolism , Caspase Inhibitors/pharmacokinetics , Caspase Inhibitors/therapeutic use , Disease Models, Animal , Half-Life , Humans , Jurkat Cells , Liver Diseases/drug therapy , Liver Diseases/pathology , Mice , Molecular Docking Simulation , Protein Structure, Tertiary , Structure-Activity Relationship , fas Receptor/antagonists & inhibitors , fas Receptor/metabolismABSTRACT
[This corrects the article DOI: 10.1021/acsmedchemlett.7b00418.].
ABSTRACT
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.