Design and synthesis of novel 3-(benzo[d]oxazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine derivatives as selective G-protein-coupled receptor kinase-2 and -5 inhibitors

Bioorg Med Chem Lett. 2013 Dec 15;23(24):6711-6. doi: 10.1016/j.bmcl.2013.10.036. Epub 2013 Oct 30.

Abstract

G-protein-coupled receptor kinase (GRK)-2 and -5 are emerging therapeutic targets for the treatment of cardiovascular disease. In our efforts to discover novel small molecules to inhibit GRK-2 and -5, a class of compound based on 3-(benzo[d]oxazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine was identified as a novel hit by high throughput screening campaign. Structural modification of parent benzoxazole scaffolds by introducing substituents on phenyl displayed potent inhibitory activities toward GRK-2 and -5.

Keywords: Benzoxazole; G-protein-coupled receptor kinase-2 (GRK-2); GRK-5; Heart failure.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amines / chemistry*
  • Benzoxazoles / chemistry
  • Binding Sites
  • Catalytic Domain
  • Drug Design*
  • Enzyme Activation / drug effects
  • G-Protein-Coupled Receptor Kinase 2 / antagonists & inhibitors*
  • G-Protein-Coupled Receptor Kinase 2 / metabolism
  • G-Protein-Coupled Receptor Kinase 5 / antagonists & inhibitors*
  • G-Protein-Coupled Receptor Kinase 5 / metabolism
  • Molecular Docking Simulation
  • Protein Binding
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrazoles / chemistry
  • Pyridines / chemistry
  • Structure-Activity Relationship

Substances

  • Amines
  • Benzoxazoles
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyridines
  • pyrazole
  • G-Protein-Coupled Receptor Kinase 2
  • G-Protein-Coupled Receptor Kinase 5
  • pyridine