Identification and Optimization of Pyrrolo[3,2-d]pyrimidine Toll-like Receptor 7 (TLR7) Selective Agonists for the Treatment of Hepatitis B

  • J Med Chem. 2017 Jul 27;60(14):6137-6151. doi: 10.1021/acs.jmedchem.7b00365.
David C McGowan  1 ,  Florence Herschke  1 ,  Frederik Pauwels  1 ,  Bart Stoops  1 ,  Ilham Smyej  1 ,  Stefaan Last  1 ,  Serge Pieters  1 ,  Werner Embrechts  1 ,  Mourad Daoubi Khamlichi  2 ,  Tine Thoné  1 ,  Bertrand Van Schoubroeck  1 ,  Wendy Mostmans  1 ,  Debbie Wuyts  1 ,  Dorien Verstappen  1 ,  Annick Scholliers  1 ,  Dorien De Pooter  1 ,  Deborah Dhuyvetter  1 ,  Herman Borghys  1 ,  Marianne Tuefferd  1 ,  Eric Arnoult  3 ,  Jin Hong  4 ,  Gregory Fanning  1 ,  Jacques Bollekens  1 ,  Vijay Urmaliya  1 ,  Ard Teisman  1 ,  Helen Horton  1 ,  Tim H M Jonckers  1 ,  Pierre Raboisson  1
Affiliations
  • 1. Janssen Pharmaceutica , N. V. Turnhoutseweg 30, 2340 Beerse, Belgium.
  • 2. Villapharma Research S.L. , Parque Tecnológico de Fuente Álamo, Ctra. El Estrecho-Lobosillo, Km. 2.5-Av. Azul, 30320 Fuente Álamo de Murcia, Murcia, Spain.
  • 3. Janssen Research & Development L.L.C. , 1400 McKean Road, Spring House, Pennsylvania 19454, United States.
  • 4. Alios Biopharma, Inc. , 260 East Grand Avenue, South San Francisco, California 94080, United States.
PMID: 28671847 DOI: 10.1021/acs.jmedchem.7b00365
Abstract

Pyrrolo[3,2-d]pyrimidines were identified as a new series of potent and selective TLR7 agonists. Compounds were optimized for their activity and selectivity over TLR8. This presents an advantage over recently described scaffolds that have residual TLR8 activity, which may be detrimental to the tolerability of the candidate drug. Oral administration of the lead compound 54 effectively induced a transient interferon stimulated gene (ISG) response in mice and cynomolgus monkeys. We aimed for a high first pass effect, limiting cytokine induction systemically, and demonstrated the potential for the immunotherapy of viral hepatitis.

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