Trifluoromethylpyrimidine-based inhibitors of proline-rich tyrosine kinase 2 (PYK2): structure-activity relationships and strategies for the elimination of reactive metabolite formation

Bioorg Med Chem Lett. 2008 Dec 1;18(23):6071-7. doi: 10.1016/j.bmcl.2008.10.030. Epub 2008 Oct 11.


The synthesis and SAR for a series of diaminopyrimidines as PYK2 inhibitors are described. Using a combination of library and traditional medicinal chemistry techniques, a FAK-selective chemical series was transformed into compounds possessing good PYK2 potency and 10- to 20-fold selectivity against FAK. Subsequent studies found that the majority of the compounds were positive in a reactive metabolite assay, an indicator for potential toxicological liabilities. Based on the proposed mechanism for bioactivation, as well as a combination of structure-based drug design and traditional medicinal chemistry techniques, a follow-up series of PYK2 inhibitors was identified that maintained PYK2 potency, FAK selectivity and HLM stability, yet were negative in the RM assay.

MeSH terms

  • Animals
  • Combinatorial Chemistry Techniques
  • Crystallography, X-Ray
  • Disease Models, Animal
  • Drug Design
  • Focal Adhesion Kinase 2 / antagonists & inhibitors*
  • Focal Adhesion Protein-Tyrosine Kinases / antagonists & inhibitors
  • Humans
  • Molecular Conformation
  • Molecular Structure
  • Osteoporosis / drug therapy
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Rats
  • Structure-Activity Relationship


  • Pyrimidines
  • Focal Adhesion Kinase 2
  • Focal Adhesion Protein-Tyrosine Kinases