Discovery of 3,3′-Spiro[Azetidine]-2-oxo-indoline Derivatives as Fusion Inhibitors for Treatment of RSV Infection

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 <b>14h</b>, which exhibited excellent <i>in vitro</i> potency with an EC₅₀ value of 0.8 nM and demonstrated 71% oral bioavailability in mice. In a mouse challenge model of RVS infection, <b>14h</b> demonstrated superior efficacy with a 3.9log RSV virus load reduction in the lung following an oral dose of 50 mg/kg.