Selective inducible microsomal prostaglandin E(2) synthase-1 (mPGES-1) inhibitors derived from an oxicam template

Bioorg Med Chem Lett. 2010 Mar 1;20(5):1604-9. doi: 10.1016/j.bmcl.2010.01.060. Epub 2010 Jan 25.

Abstract

Here we describe the SAR of a series of potent and selective mPGES-1 inhibitors based on an oxicam template. Compound 13j demonstrated low nanomolar mPGES-1 inhibition in an enzyme assay. In addition, it displayed PGE(2) inhibition in a cell-based assay (0.42microM) and had over 238-fold selectivity for mPGES-1 over COX-2 and over 200-fold selectivity for mPGES-1 over 6-keto PGF(1alpha).

MeSH terms

  • Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry*
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Cell Line
  • Cyclic S-Oxides / chemical synthesis
  • Cyclic S-Oxides / chemistry*
  • Cyclic S-Oxides / pharmacology
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Intramolecular Oxidoreductases / antagonists & inhibitors*
  • Intramolecular Oxidoreductases / metabolism
  • Prostaglandin-E Synthases
  • Structure-Activity Relationship
  • Thiazines / chemical synthesis
  • Thiazines / chemistry*
  • Thiazines / pharmacology

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Cyclic S-Oxides
  • Enzyme Inhibitors
  • Thiazines
  • Intramolecular Oxidoreductases
  • PTGES protein, human
  • Prostaglandin-E Synthases