Discovery of 33′-SpiroAzetidine-2-oxo-indolineDerivatives as Fusion Inhibitors for Treatment of RSV Infection

摘要

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.