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. Epub 2018 Jan 16.

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.

MeSH terms

  • Animals
  • Cytochrome P-450 Enzyme Inhibitors / chemical synthesis
  • Cytochrome P-450 Enzyme Inhibitors / chemistry
  • Cytochrome P-450 Enzyme Inhibitors / pharmacokinetics
  • Cytochrome P-450 Enzyme Inhibitors / pharmacology
  • HEK293 Cells
  • Half-Life
  • Humans
  • Interferon-alpha / metabolism
  • Male
  • Membrane Glycoproteins / agonists*
  • Mice, Inbred C57BL
  • Microsomes, Liver / metabolism
  • Molecular Docking Simulation
  • Molecular Structure
  • Quinazolines / chemical synthesis
  • Quinazolines / chemistry
  • Quinazolines / pharmacokinetics
  • Quinazolines / pharmacology*
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship
  • Toll-Like Receptor 7 / agonists*
  • Toll-Like Receptor 8 / agonists

Substances

  • Cytochrome P-450 Enzyme Inhibitors
  • Interferon-alpha
  • Membrane Glycoproteins
  • Quinazolines
  • TLR7 protein, human
  • TLR7 protein, rat
  • TLR8 protein, human
  • TLR8 protein, mouse
  • Tlr7 protein, mouse
  • Toll-Like Receptor 7
  • Toll-Like Receptor 8