Purine derivatives as potent Bruton's tyrosine kinase (BTK) inhibitors for autoimmune diseases

Bioorg Med Chem Lett. 2014 May 1;24(9):2206-11. doi: 10.1016/j.bmcl.2014.02.075. Epub 2014 Mar 13.

Abstract

Investigation of various heterocyclic core isosteres of imidazopyrazines 1 & 2 yielded purine derivatives 3 & 8 as potent and selective BTK inhibitors. Subsequent SAR studies of the purine series led to the discovery of 20 as a leading compound. Compound 20 is very selective when screened against a panel of 400 kinases and is a potent inhibitor in cellular assays of human B cell function including B-Cell proliferation and CD86 cell surface expression and exhibited in vivo efficacy in a mouse PCA model. Its X-ray co-crystal structure with BTK shows that the high selectivity is gained from filling a BTK specific lipophilic pocket. However, physical and ADME properties leading to low oral exposure hindered further development.

Keywords: Autoimmune diseases; BTK; Purine.

MeSH terms

  • Agammaglobulinaemia Tyrosine Kinase
  • Animals
  • Autoimmune Diseases / drug therapy
  • Autoimmune Diseases / enzymology
  • B-Lymphocytes / drug effects
  • Crystallography, X-Ray
  • Humans
  • Mice
  • Models, Molecular
  • Passive Cutaneous Anaphylaxis / drug effects
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / metabolism
  • Purines / chemistry*
  • Purines / pharmacology*
  • Rats

Substances

  • Protein Kinase Inhibitors
  • Purines
  • Protein-Tyrosine Kinases
  • Agammaglobulinaemia Tyrosine Kinase
  • BTK protein, human
  • Btk protein, mouse