Novel benzoxazole inhibitors of mPGES-1

Bioorg Med Chem Lett. 2013 Feb 1;23(3):907-11. doi: 10.1016/j.bmcl.2012.10.040. Epub 2012 Oct 16.

Abstract

A novel series of potent benzoxazole mPGES-1 inhibitors has been derived from a hit from a high throughput screen. Compound 37 displays mPGES-1 inhibition in an enzyme assay (0.018 μM) and PGE-2 inhibition in a cell-based assay (0.034 μM). It demonstrates 500- and 2500-fold selectivity for mPGES-1 over COX-2 and 6-keto PGF-1α, respectively. In vivo PK studies in dogs demonstrate 55% oral bioavailability and an 7 h half-life.

MeSH terms

  • Amides / chemical synthesis
  • Amides / chemistry
  • Amides / pharmacology
  • Animals
  • Benzoxazoles / chemical synthesis
  • Benzoxazoles / chemistry*
  • Benzoxazoles / pharmacokinetics
  • Benzoxazoles / pharmacology
  • Biological Availability
  • Dogs
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Inhibitory Concentration 50
  • Intramolecular Oxidoreductases / antagonists & inhibitors*
  • Molecular Structure
  • Prostaglandin-E Synthases
  • Structure-Activity Relationship

Substances

  • Amides
  • Benzoxazoles
  • Enzyme Inhibitors
  • Intramolecular Oxidoreductases
  • PTGES protein, human
  • Prostaglandin-E Synthases