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

J Med Chem. 2021 Apr 8;64(7):3658-3676. doi: 10.1021/acs.jmedchem.0c01882.

G Stuart Cockerill ¹, Richard M Angell ², Alexandre Bedernjak ¹, Irina Chuckowree ², Ian Fraser ¹, Jose Gascon-Simorte ², Morgan S A Gilman ³, James A D Good ¹, Rachel Harland ¹, Sara M Johnson ⁴, John H Ludes-Meyers ³, Edward Littler ¹, James Lumley ¹, Graham Lunn ², Neil Mathews ¹, Jason S McLellan ³, Michael Paradowski ⁵, Mark E Peeples ⁴, Claire Scott ¹, Dereck Tait ¹, Geraldine Taylor ⁶, Michelle Thom ⁶, Elaine Thomas ¹, Carol Villalonga Barber ², Simon E Ward ⁵, Daniel Watterson ⁷, Gareth Williams ², Paul Young ⁷, Kenneth Powell ¹

Affiliations

1 Reviral Ltd., Stevenage Bioscience Catalyst, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2FX, U.K.
2 Sussex Drug Discovery Centre, University of Sussex, Brighton, England BN1 9QJ, U.K.
3 Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas 78712, United States.
4 Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, and Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio 43205, United States.
5 Medicines Discovery Institute, Cardiff University, Cardiff, Wales CF10 3AT, U.K.
6 The Pirbright Institute, Ash Road, Pirbright, Surrey GU24 0NF, U.K.
7 School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland 4072, Australia.

PMID: 33729773 DOI: 10.1021/acs.jmedchem.0c01882

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.

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