Structure-activity relationships for inhibition of prostaglandin cyclooxygenase by phenolic compounds.

Sixty-three phenolic compounds were examined for their ability to inhibit sheep vesicular gland prostaglandin cyclooxygenase. Examination of structure-activity relationships for these compounds indicated that inhibition was increased by ring substituents which were electron donating and by substituents which were hydrophobic. Inhibition was decreased by steric masking of the phenolic hydroxyl. The most potent inhibitors possessed a two aromatic ring structure connected by a short bridge. In these inhibitors, one ring was apolar, the other ring contained a phenolic hydroxyl ortho to the bridge, and the bridge contained a Lewis base such that the compounds could form bidentate metal chelates. Compounds with [I]50 values of less than 10 mM included 2,4,6-trimethylphenol, 7.2 microM; 2-(2-hydroxyphenyl)benzothiazole, 7.0 microM; 2-benzyloxyphenol, 5.2 microM; and 2-hydroxybenzophenone, 3.8 microM. Inhibition of arachidonate induced platelet aggregation was examined for three of the more potent inhibitors. 2-Benzyloxyphenol and 2,4,6-trimethylphenol were more potent than indomethacin when assayed using a 2 min preincubation of inhibitor with platelets.