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Discovery of sisunatovir (RV521), an inhibitor of respiratory syncytial virus fusion

Cockerill, G. Stuart, Angell, Richard M., Bedernjak, Alexandre, Chuckowree, Irina, Fraser, Ian, Gascon-Simorte, Jose, Gilman, Morgan S. A., Good, James A. D., Harland, Rachel, Johnson, Sara M., Ludes-Meyers, John H, Littler, Edward, Lumley, James, Lunn, Graham, Mathews, Neil, McLellan, Jason S., Paradowski, Michael, Peeples, Mark E., Scott, Claire, Tait, Dereck, Taylor, Geraldine, Thom, Michelle, Thomas, Elaine, Villalonga Barber, Carol, Ward, Simon E., Watterson, Daniel, Williams, Gareth, Young, Paul and Powell, Kenneth 2021. Discovery of sisunatovir (RV521), an inhibitor of respiratory syncytial virus fusion. Journal of Medicinal Chemistry 64 (7) , pp. 3658-3676. 10.1021/acs.jmedchem.0c01882
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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Publisher: American Chemical Society
ISSN: 0022-2623
Date of First Compliant Deposit: 6 August 2021
Last Modified: 06 Aug 2021 08:02
URI: http://orca.cardiff.ac.uk/id/eprint/143067

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