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

J V Duncia; J B Santella 3rd; C A Higley; W J Pitts; J Wityak; W E Frietze; F W Rankin; J H Sun; R A Earl; A C Tabaka; C A Teleha; K F Blom; M F Favata; E J Manos; A J Daulerio; D A Stradley; K Horiuchi; R A Copeland; P A Scherle; J M Trzaskos; R L Magolda; G L Trainor; R R Wexler; F W Hobbs; R E Olson

doi:10.1016/s0960-894x(98)00522-8

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.

Affiliation

¹ DuPont Pharmaceuticals Company, Chemical and Physical Sciences Department, Wilmington, DE 19880, USA.

PMID: 9873633
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