1-(5-Chloro-2-alkoxyphenyl)-3-(5-cyanopyrazin-2-yl)ureas [correction of cyanopyrazi] as potent and selective inhibitors of Chk1 kinase: synthesis, preliminary SAR, and biological activities

J Med Chem. 2005 May 5;48(9):3118-21. doi: 10.1021/jm048989d.

Abstract

The discovery of 1-(5-chloro-2-alkoxyphenyl)-3-(5-cyanopyrazin-2-yl)ureas as a new class of potent (IC(50) values of 3-10 nM) and selective inhibitors of Chk1 kinase was described. One of these compounds (2e) potentiates HeLa cells by over 22-fold against doxorubicin in an antiproliferation assay, and SW620 cells against camptothecin by 20-fold in an antiproliferation assay and 14-fold in a soft agar assay. Flow cytometry (FACS) analysis confirmed that 2e abrogated G2 checkpoint arrest of H1299 cells caused by doxorubicin and S checkpoint arrest caused by camptothecin.

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Camptothecin / pharmacology
  • Cell Cycle / drug effects
  • Checkpoint Kinase 1
  • Crystallography, X-Ray
  • Doxorubicin / pharmacology
  • Drug Screening Assays, Antitumor
  • HeLa Cells
  • Humans
  • Nitriles / chemical synthesis*
  • Nitriles / pharmacology
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinases / metabolism*
  • Pyrazoles / chemical synthesis*
  • Pyrazoles / pharmacology
  • Structure-Activity Relationship
  • Urea / analogs & derivatives*
  • Urea / chemical synthesis*
  • Urea / pharmacology

Substances

  • Antineoplastic Agents
  • Nitriles
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Doxorubicin
  • Urea
  • Protein Kinases
  • CHEK1 protein, human
  • Checkpoint Kinase 1
  • Camptothecin