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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