MEK inhibitors: the chemistry and biological activity of U0126, its analogs, and cyclization products

Bioorg Med Chem Lett. 1998 Oct 20;8(20):2839-44. doi: 10.1016/s0960-894x(98)00522-8.

Abstract

In search of antiinflammatory drugs with a new mechanism of action, U0126 was found to functionally antagonize AP-1 transcriptional activity via noncompetitive inhibition of the dual specificity kinase MEK with an IC50 of 0.07 microM for MEK 1 and 0.06 microM for MEK 2. U0126 can undergo isomerization and cyclization reactions to form a variety of products, both chemically and in vivo, all of which exhibit less affinity for MEK and lower inhibition of AP-1 activity than parent, U0126.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / chemistry
  • Anti-Inflammatory Agents / pharmacokinetics
  • Anti-Inflammatory Agents / pharmacology
  • Biotransformation
  • Butadienes / chemistry*
  • Butadienes / pharmacokinetics
  • Butadienes / pharmacology
  • Cyclization
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology
  • NF-kappa B / antagonists & inhibitors
  • Nitriles / chemistry*
  • Nitriles / pharmacokinetics
  • Nitriles / pharmacology
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Rats
  • Transcription Factor AP-1 / antagonists & inhibitors

Substances

  • Anti-Inflammatory Agents
  • Butadienes
  • Enzyme Inhibitors
  • NF-kappa B
  • Nitriles
  • Transcription Factor AP-1
  • U 0126
  • Protein-Serine-Threonine Kinases