Design, synthesis, and pharmacological evaluation of quinazoline derivatives as novel and potent pan-JAK inhibitors

Bioorg Chem. 2023 Nov:140:106765. doi: 10.1016/j.bioorg.2023.106765. Epub 2023 Aug 7.

Abstract

Janus kinases (JAKs) play a critical role in modulating the function and expression of inflammatory cytokines related to rheumatoid arthritis (RA). Herein, we report the design, synthesis, and structure-activity relationships (SARs) of a series of novel quinazoline derivatives as JAK inhibitors. Among these inhibitors, compound 11n showed high potency against JAKs (JAK1/JAK2/JAK3/TYK2, IC50 = 0.40, 0.83, 2.10, 1.95 nM), desirable metabolic characters, and excellent pharmacokinetic properties. In collagen-induced arthritis (CIA) models, compound 11n exhibited significant reduction in joint swelling with good safety, which could be served as a potential therapeutic candidate for the treatment of inflammatory diseases.

Keywords: Anti-inflammation; JAK inhibitor; Quinazoline; Rheumatoid arthritis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arthritis, Rheumatoid* / drug therapy
  • Humans
  • Janus Kinase Inhibitors* / pharmacology
  • Janus Kinase Inhibitors* / therapeutic use
  • Janus Kinases
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Quinazolines / pharmacology
  • Quinazolines / therapeutic use
  • Structure-Activity Relationship

Substances

  • Janus Kinase Inhibitors
  • Quinazolines
  • Janus Kinases
  • Protein Kinase Inhibitors