Discovery of Sisunatovir (RV521), an Inhibitor of Respiratory Syncytial Virus Fusion
G. Stuart Cockerill, Richard Angell, Alexandre F. Bedernjak, Irina Chuckowree, Ian S. Fraser, Jose M. Gascon-Simorte, Morgan S. A. Gilman, James A. D. Good, Rachel Harland, Sara M. Johnson, John Ludes-Meyers, Edward Littler, James A. Lumley, Graham Lunn, Neil Mathews, Jason S. McLellan, Michael Paradowski, Mark E. Peeples, Claire Scott, Dereck Tait, Geraldine Taylor, Michelle Thom, E. Donnall Thomas, Carol Villalonga Barber, Simon E. Ward, Daniel Watterson, Gareth Williams, Paul R. Young, Kenneth L. Powell
Abstract
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.