Approaching the active conformation of 1,3-diaminopyrimidine based covalent inhibitors of Bruton's tyrosine kinase for treatment of Rheumatoid arthritis

Bioorg Med Chem Lett. 2016 Apr 15;26(8):1954-7. doi: 10.1016/j.bmcl.2016.03.011. Epub 2016 Mar 4.

Abstract

By applying conformational restrictions, we were able to discover highly potent 1,3-diaminopyrimidine based covalent inhibitors of BTK, such as 8a (IC50=3.76 nM), and providing useful information of its active conformation. We are developing these novel small molecule covalent inhibitors of BTK toward oral agents for Rheumatoid arthritis.

Keywords: 1,3-Diamino-pyrimidine; Bruton’s tyrosine kinase (BTK); Collagen-induced arthritis (CIA); Rheumatoid arthritis (RA).

MeSH terms

  • Agammaglobulinaemia Tyrosine Kinase
  • Animals
  • Arthritis, Rheumatoid / drug therapy*
  • Arthritis, Rheumatoid / metabolism
  • Dogs
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Conformation
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / metabolism
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship

Substances

  • 1,3-diaminopyrimidine
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Protein-Tyrosine Kinases
  • Agammaglobulinaemia Tyrosine Kinase
  • BTK protein, human