Amino acid derived quinazolines as Rock/PKA inhibitors

Bioorg Med Chem Lett. 2013 Mar 15;23(6):1592-9. doi: 10.1016/j.bmcl.2013.01.109. Epub 2013 Jan 31.

Abstract

SAR and lead optimization studies for Rock inhibitors based on amino acid-derived quinazolines are described. Studies demonstrated that these amino acid derived quinazolinones were mainly pan-Rock (I & II) inhibitors. While selectivity against other kinases could be achieved, selectivity for most of these compounds against PKA was not achieved. This is distinct from Rock inhibitors based on non-amino acid derived quinazolinones, where high selectivity against PKA could be obtained.(22) The inhibitors presented here in some cases possessed sub-nanomolar inhibition of Rock, nanomolar potency in ppMLC cell based assays, low to fair cytochrome P-450 inhibition, and good human microsomal stability.

MeSH terms

  • Amino Acids / chemistry*
  • Binding Sites
  • Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors*
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Humans
  • Microsomes / metabolism
  • Molecular Docking Simulation
  • Protein Binding
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / metabolism
  • Protein Structure, Tertiary
  • Quinazolines / chemical synthesis
  • Quinazolines / chemistry*
  • Quinazolines / metabolism
  • Structure-Activity Relationship
  • rho-Associated Kinases / antagonists & inhibitors*
  • rho-Associated Kinases / metabolism

Substances

  • Amino Acids
  • Protein Kinase Inhibitors
  • Quinazolines
  • rho-Associated Kinases
  • Cyclic AMP-Dependent Protein Kinases