Design and synthesis of tricyclic cores for kinase inhibition

Bioorg Med Chem Lett. 2013 Feb 1;23(3):693-8. doi: 10.1016/j.bmcl.2012.11.108. Epub 2012 Dec 5.

Abstract

Interest in therapeutic kinase inhibitors continues to grow beyond success in oncology. To date, ATP-mimetic kinase inhibitors have focused primarily on monocyclic and bicyclic heterocyclic cores. We sought to expand on the repertoire of potential cores for kinase inhibition by exploring tricyclic variants of classical bicyclic hinge binding motifs such as pyrrolopyridine and pyrrolopyrazine. Herein we describe the syntheses of eight alternative tricyclic cores as well as in vitro screening results for representative kinases of potential therapeutic interest.

MeSH terms

  • Cells, Cultured
  • Cyclization
  • Drug Design*
  • Enzyme Activation / drug effects
  • Inhibitory Concentration 50
  • Molecular Structure
  • Protein Kinase Inhibitors* / chemical synthesis
  • Protein Kinase Inhibitors* / chemistry
  • Protein Kinase Inhibitors* / pharmacology
  • Pyrazines / chemical synthesis
  • Pyrazines / chemistry
  • Pyrazines / pharmacology
  • Pyridines / chemical synthesis
  • Pyridines / chemistry
  • Pyridines / pharmacology
  • Pyrroles / chemical synthesis
  • Pyrroles / chemistry
  • Pyrroles / pharmacology

Substances

  • Protein Kinase Inhibitors
  • Pyrazines
  • Pyridines
  • Pyrroles