Discovery of selective 2,4-diaminoquinazoline toll-like receptor 7 (TLR 7) agonists

  • Bioorg Med Chem Lett. 2018 Feb 15;28(4):711-719. doi: 10.1016/j.bmcl.2018.01.014.
Serge Pieters  1 ,  David McGowan  2 ,  Florence Herschke  2 ,  Frederik Pauwels  2 ,  Bart Stoops  2 ,  Stefaan Last  2 ,  Werner Embrechts  2 ,  Annick Scholliers  2 ,  Wendy Mostmans  2 ,  Kris Van Dijck  2 ,  Bertrand Van Schoubroeck  2 ,  Tine Thoné  2 ,  Dorien De Pooter  2 ,  Gregory Fanning  2 ,  Mari Luz Rosauro  3 ,  Mourad Daoubi Khamlichi  3 ,  Ioannis Houpis  2 ,  Eric Arnoult  4 ,  Tim H M Jonckers  2 ,  Pierre Raboisson  2
Affiliations
  • 1. Janssen Infectious Diseases Diagnostics BVBA, Turnhoutseweg 30, 2340 Beerse, Belgium. Electronic address: [email protected].
  • 2. Janssen Infectious Diseases Diagnostics BVBA, Turnhoutseweg 30, 2340 Beerse, Belgium.
  • 3. 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.
  • 4. Janssen Research & Development L.L.C., 1400 McKean Rd, Spring House, PA 19454, United States.
PMID: 29366653 DOI: 10.1016/j.bmcl.2018.01.014
Abstract

The discovery of a novel series of highly potent quinazoline TLR 7/8 agonists is described. The synthesis and structure-activity relationship is presented. Structural requirements and optimization of this series toward TLR 7 selectivity afforded the potent agonist 48. Pharmacokinetic and pharmacodynamic studies highlighted 48 as an orally available endogenous interferon (IFN-α) inducer in mice.

Keywords
HBV; Quinazoline; TLR7.
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