Etodolac, a novel antiinflammatory agent. The syntheses and biological evaluation of its metabolites

J Med Chem. 1988 Sep;31(9):1712-9. doi: 10.1021/jm00117a009.

Abstract

The syntheses of five metabolites of the antiinflammatory drug etodolac (1,8-diethyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-1-acetic acid) are described, viz. 6-hydroxyetodolac, N-methyletodolac, 4-ureidoetodolac, 8-(1'-hydroxy)etodolac, and 4-oxoetodolac. These syntheses were used to confirm the identities of the metabolites. The metabolites themselves, as well as the previously reported metabolite 7-hydroxyetodolac, were tested in a rat adjuvant edema model and in vitro for their capacity to block prostaglandin production in chondrocyte cells. All either were inactive or possessed only marginal activity. The isolation of N-methyletodolac and 4-oxoetodolac from human and rat urine, respectively, is also described.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal
  • Cartilage / drug effects
  • Cartilage / metabolism
  • Cells, Cultured
  • Chemical Phenomena
  • Chemistry
  • Chromatography, High Pressure Liquid
  • Dinoprostone
  • Edema / drug therapy
  • Etodolac
  • Humans
  • Indoleacetic Acids / chemical synthesis*
  • Indoleacetic Acids / pharmacology
  • Indoleacetic Acids / urine
  • Male
  • Methylation
  • Oxidation-Reduction
  • Prostaglandins E / biosynthesis
  • Rats
  • Rats, Inbred Strains
  • Stereoisomerism

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Indoleacetic Acids
  • Prostaglandins E
  • Etodolac
  • Dinoprostone