Discovery of Acyl-Indole Derivatives as Pan-Serotype Dengue Virus NS4B Inhibitors

In
the absence of any approved dengue-specific treatment, the discovery
and development of a novel small-molecule antiviral for the prevention
or treatment of dengue are critical. We previously reported the identification
of a novel series of 3-acyl-indole derivatives as potent and pan-serotype
dengue virus inhibitors. We herein describe our optimization efforts
toward preclinical candidates 24a and 28a with improved pan-serotype coverage (EC50’s against
the four DENV serotypes ranging from 0.0011 to 0.24 μM for 24a and from 0.00060 to 0.084 μM for 28a), chiral stability, and oral bioavailability in preclinical species,
as well as showing a dose-proportional increase in efficacy against
DENV-2 infection in vivo in mice.