2. Academic Validation
  3. Discovery of 3-({5-Chloro-1-[3-(methylsulfonyl)propyl]-1 H-indol-2-yl}methyl)-1-(2,2,2-trifluoroethyl)-1,3-dihydro-2 H-imidazo[4,5- c]pyridin-2-one (JNJ-53718678), a Potent and Orally Bioavailable Fusion Inhibitor of Respiratory Syncytial Virus

Discovery of 3-({5-Chloro-1-[3-(methylsulfonyl)propyl]-1 H-indol-2-yl}methyl)-1-(2,2,2-trifluoroethyl)-1,3-dihydro-2 H-imidazo[4,5- c]pyridin-2-one (JNJ-53718678), a Potent and Orally Bioavailable Fusion Inhibitor of Respiratory Syncytial Virus

  • J Med Chem. 2020 Aug 13;63(15):8046-8058. doi: 10.1021/acs.jmedchem.0c00226.
Sandrine Vendeville 1,  Abdellah Tahri 1,  Lili Hu 1,  Samuel Demin 1,  Ludwig Cooymans 1,  Ann Vos 1,  Leen Kwanten 1,  Joke Van den Berg 1,  Michael B Battles 2,  Jason S McLellan 3,  Anil Koul 1,  Pierre Raboisson 1,  Dirk Roymans 1,  Tim H M Jonckers 1
Affiliations

Affiliations

  • 1 Janssen Pharmaceutica NV, Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340 Beerse, Belgium.
  • 2 Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755, United States.
  • 3 Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas 78712, United States.
PMID: 32407115 DOI: 10.1021/acs.jmedchem.0c00226
Abstract

Respiratory syncytial virus (RSV) is a seasonal virus that infects the lungs and airways of 64 million children and adults every year. It is a major cause of acute lower respiratory tract Infection and is associated with significant morbidity and mortality. Despite the large medical and economic burden, treatment options for RSV-associated bronchiolitis and pneumonia are limited and mainly consist of supportive care. This publication covers the medicinal chemistry efforts resulting in the identification of JNJ-53718678, an orally bioavailable RSV Inhibitor that was shown to be efficacious in a phase 2a challenge study in healthy adult subjects and that is currently being evaluated in hospitalized infants and adults. Cocrystal structures of several new derivatives helped in rationalizing some of the structure-activity relationship (SAR) trends observed.

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