Discovery of Sisunatovir (RV521), an Inhibitor of Respiratory Syncytial Virus Fusion

RV521 is an orally bioavailable inhibitor
of respiratory syncytial virus
(RSV) fusion that was identified
after a lead optimization process based upon hits that originated
from a physical property directed hit profiling exercise at Reviral.
This exercise encompassed collaborations with a number of contract
organizations with collaborative medicinal chemistry and virology
during the optimization phase in addition to those utilized as the
compound proceeded through preclinical and clinical evaluation. RV521
exhibited a mean IC50 of 1.2 nM against a panel of RSV
A and B laboratory strains and clinical isolates with antiviral efficacy
in the Balb/C mouse model of RSV infection. Oral bioavailability in
preclinical species ranged from 42 to >100% with evidence of highly
efficient penetration into lung tissue. In healthy adult human volunteers
experimentally infected with RSV, a potent antiviral effect was observed
with a significant reduction in viral load and symptoms compared to
placebo.