9,11-Epoxy-9-homo-14-oxaprosta-5-enoic acid derivatives. Novel inhibitors of fatty acid cyclooxygenase

J Med Chem. 1986 Nov;29(11):2335-47. doi: 10.1021/jm00161a032.

Abstract

A novel bicyclic prostaglandin analogue, [1R-[l alpha,2 beta (5Z),3 beta,4 alpha]]-7-[3-[(hexyloxy)methyl]- 7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (1), and cogeners were found to be potent inhibitors of fatty acid cyclooxygenase. Compound 1 was the only stereoisomer out of eight possible structures that was active. Ether 1 was 20 times more potent than indomethacin (IND) in inhibiting arachidonic acid (AA) induced aggregation of human platelet-rich plasma. Compound 1 was also more potent than IND in several in vivo assays, AA-induced sudden death in the conscious mouse (2 times) and AA-induced bronchoconstriction in the anesthetized guinea pig (16-45 times).

MeSH terms

  • Arachidonic Acid
  • Arachidonic Acids / pharmacology
  • Cyclooxygenase Inhibitors*
  • Humans
  • Indomethacin / pharmacology
  • Molecular Conformation
  • Platelet Aggregation / drug effects
  • Prostaglandins, Synthetic / chemical synthesis*
  • Prostaglandins, Synthetic / pharmacology
  • Structure-Activity Relationship

Substances

  • Arachidonic Acids
  • Cyclooxygenase Inhibitors
  • Prostaglandins, Synthetic
  • Arachidonic Acid
  • Indomethacin