Beyond U0126. Dianion chemistry leading to the rapid synthesis of a series of potent MEK inhibitors

Bioorg Med Chem Lett. 2004 Mar 22;14(6):1483-6. doi: 10.1016/j.bmcl.2004.01.012.

Abstract

Employing phenylmalonitrile dianion chemistry, a large number of analogues of MEK inhibitor lead SH053 (IC(50)=140 nM) were rapidly synthesized leading to single digit nM inhibitors, displaying submicromolar AP-1 transcription inhibition in COS-7 cells. Compound 41, exhibiting a MEK IC(50)=12 nM showed ip activity in a TPA-induced ear edema model with an ED(50)=5 mg/kg.

MeSH terms

  • Animals
  • Butadienes / chemical synthesis*
  • COS Cells
  • Chemistry, Pharmaceutical / methods*
  • Chlorocebus aethiops
  • Enzyme Inhibitors / chemical synthesis*
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Nitriles / chemical synthesis*
  • Structure-Activity Relationship

Substances

  • Butadienes
  • Enzyme Inhibitors
  • Nitriles
  • U 0126
  • Mitogen-Activated Protein Kinase Kinases