Discovery of gem-Dimethyl-hydroxymethylpyridine Derivatives as Potent Non-nucleoside RSV Polymerase Inhibitors

  • J Med Chem. 2024 Aug 22;67(16):13723-13736. doi: 10.1021/acs.jmedchem.4c00525.
Sandrine Grosse  1 ,  Ludwig Cooymans  1 ,  Werner Embrechts  1 ,  David McGowan  2 ,  Edgar Jacoby  1 ,  Bart Stoops  1 ,  Kusum Gupta  3 ,  Mark Ackermann  4 ,  Sarhad Alnajjar  5 ,  Jerome Guillemont  6 ,  Zhinan Jin  7 ,  Bart Kesteleyn  1 ,  Kiran Matcha  1 ,  Pun Sriboonyapirat  4 ,  Anh Truong  3 ,  Joke Van Den Berg  1 ,  Xiaodi Yu  8 ,  Florence Herschke  1 ,  Dirk Roymans  9 ,  Pierre Raboisson  10 ,  Peter Rigaux  1 ,  Tim H M Jonckers  1
Affiliations
  • 1. Janssen Research & Development, Janssen Pharmaceutica NV, 2340 Beerse, Belgium.
  • 2. Aligos, Gaston Geenslaan 1, 3001 Leuven, Belgium.
  • 3. Neuron23 Inc. 343 Oyster Point Blvd, South San Francisco, California 94080, United States.
  • 4. LambCure LLC, Corvallis, Oregon 97232, United States.
  • 5. Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7AL, U.K.
  • 6. NovAlix, 27106 Val-de-Reuil, France.
  • 7. Janssen Pharmaceutica NV, Brisbane, California 94005, United States.
  • 8. Janssen Pharmaceutica NV, Spring House, Pennsylvania 19477 United States.
  • 9. DNS Life Sciences Consulting, Brandhoefstraat 63, 2300 Turnhout, Belgium.
  • 10. Galapagos, General De Wittelaan L112, A3, 2800 Mechelen, Belgium.
PMID: 39105710 DOI: 10.1021/acs.jmedchem.4c00525
Abstract

Respiratory syncytial virus (RSV) is an RNA virus infecting the upper and lower respiratory tract and is recognized as a major respiratory health threat, particularly to older adults, immunocompromised individuals, and young children. Around 64 million children and adults are infected every year worldwide. Despite two vaccines and a new generation monoclonal antibody recently approved, no effective Antiviral treatment is available. In this manuscript, we present the medicinal chemistry efforts resulting in the identification of compound 28 (JNJ-8003), a novel RSV non-nucleoside inhibitor displaying subnanomolar activity in vitro as well as prominent efficacy in mice and a neonatal lamb models.

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