Diphenylmethylazine prostanoids with prostacyclin-like actions on human platelets

Abstract

A structure-activity study has been performed with respect to EP 157, a PGH2 analogue with a diphenylmethoxime omega-chain which behaves as an IP-receptor agonist. Bicyclo[2.2.1]heptene/heptane and bicyclo[2.2.2]octene/octane analogues were the most potent, with a cyclohexene analogue being less potent. Oxabicyclo[3.2.2]nonane, oxabicyclo[3.2.1]octane and oxabicyclo[2.2.1]heptane analogues were of low potency. Introduction of ether oxygen(s) into the omega-chain generally maintained potency, whereas 6-oxa-1,4-m- and 6-oxa-1,4-p-interphenylene analogues were inactive. Diphenylmethylazine analogues were also potent platelet inhibitors, but saturation of one of the phenyl rings abolished activity. Replacement of the oxime function by an ether group abolished activity. The results are discussed in relation to octimibate, a triphenylimidazoloxyalkanoic acid which is also an IP-receptor agonist, and to the possibility of IP-receptor subtypes.