Optimisation of momelotinib with improved potency and efficacy as pan-JAK inhibitor

Bioorg Med Chem Lett. 2022 Jun 15:66:128728. doi: 10.1016/j.bmcl.2022.128728. Epub 2022 Apr 9.

Abstract

Dysregulated JAK-STAT signaling has been proven to be involved in several immune-mediated diseases. Several janus kinase (JAK) inhibitors have been approved for the treatment of various inflammatory and autoimmune diseases such as rheumatoid arthritis (RA), plaque psoriasis, psoriatic arthritis, inflammatory bowel disease (IBD). Here, we report the design, optimisation, synthesis and biological evaluation of momelotinib analogues (a pyrimidine based JAK inhibitor), to get pan-JAK inhibitors. Systematic structure activity relationship studies led to the discovery of compound 32, which potently inhibited JAK1, JAK2 and JAK3. The in vivo investigation indicated that compound 32 possessed favourable pharmacokinetic properties and displayed superior anti-inflammatory efficacy than momelotinib 1. Accordingly, compound 32 was advanced into preclinical development.

Keywords: Inflammation; JAK inhibitor; Momelotinib; Pyrimidine.

MeSH terms

  • Benzamides
  • Humans
  • Immune System Diseases*
  • Janus Kinase Inhibitors* / therapeutic use
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use

Substances

  • Benzamides
  • Janus Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Pyrimidines
  • N-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide