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

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).