Synthesis and biological evaluation of 1-(2,4,5-trisubstituted phenyl)-3-(5-cyanopyrazin-2-yl)ureas as potent Chk1 kinase inhibitors

Bioorg Med Chem Lett. 2006 Apr 15;16(8):2293-8. doi: 10.1016/j.bmcl.2006.01.028. Epub 2006 Jan 30.

Abstract

Based on the X-ray crystallography of our lead compound 1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-cyanopyrazin-2-yl)urea in the checkpoint kinase 1 (Chk1) enzyme, we modified R4, and to a lesser extent, R2, and R5 of the phenyl ring, and made a variety of N-aryl-N'-pyrazinylurea Chk1 inhibitors. Enzymatic activity less than 20 nM was observed in 15 of 41 compounds. Compound 8i provided the best overall results in the cellular assays as it abrogated doxorubicin-induced cell cycle arrest (IC50=1.7 microM) and enhanced doxorubicin cytotoxicity (IC50=0.44 microM) while displaying no single agent activity.

Publication types

  • Evaluation Study

MeSH terms

  • Antibiotics, Antineoplastic / chemical synthesis
  • Antibiotics, Antineoplastic / pharmacology*
  • Cell Cycle / drug effects*
  • Checkpoint Kinase 1
  • Crystallography, X-Ray
  • Doxorubicin / pharmacology
  • Humans
  • Inhibitory Concentration 50
  • Nitriles / chemical synthesis
  • Nitriles / pharmacology
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinases / drug effects*
  • Protein Kinases / metabolism
  • Pyrazines / chemical synthesis
  • Pyrazines / pharmacology
  • Tumor Cells, Cultured
  • Urea / analogs & derivatives
  • Urea / chemical synthesis
  • Urea / pharmacology

Substances

  • Antibiotics, Antineoplastic
  • Nitriles
  • Protein Kinase Inhibitors
  • Pyrazines
  • Doxorubicin
  • Urea
  • Protein Kinases
  • CHEK1 protein, human
  • Checkpoint Kinase 1