N-4-Pyrimidinyl-1H-indazol-4-amine inhibitors of Lck: indazoles as phenol isosteres with improved pharmacokinetics

Bioorg Med Chem Lett. 2007 Aug 1;17(15):4363-8. doi: 10.1016/j.bmcl.2007.04.029. Epub 2007 Apr 13.


2,4-Dianilino pyrimidines are well-known inhibitors of tyrosine kinases including lymphocyte specific kinase (Lck). Structure-activity relationships at the 4-position are discussed and rationalised. Examples bearing a 2-methyl-5-hydroxyaniline substituent at the 4-position were especially potent but showed poor oral pharmacokinetics. Replacement of this substituent by 4-amino(5-methyl-1H-indazole) yielded compounds with comparable enzyme potency and improved pharmacokinetic properties.

MeSH terms

  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • Indazoles / pharmacokinetics
  • Indazoles / pharmacology*
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / antagonists & inhibitors*
  • Models, Molecular


  • Enzyme Inhibitors
  • Indazoles
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck)