Abstract

Decreased synthesis of arachidonic acid by inhibition of the Δ6 or Δ5 desaturase was evaluated as a means to mitigate inflammation. Using quantitative in vitro and in vivoradioassays, novel compounds representing five classes of Δ5 desaturase inhibitors and one class of Δ6 desaturase inhibitor were identified. The Δ6 desaturase inhibitor, SC-26196, had pharmacokinetic and pharmacodynamic profiles in mice that allowed for the evaluation of the pharmacological effects of chronic inhibition of desaturase activity. SC-26196 decreased edema to the same extent as indomethacin or essential fatty acid deficiency in the carrageenan paw edema model in the mouse. The antiinflammatory properties of SC-26196 were consistent with its mechanism of action as a Δ6 desaturase inhibitor: 1) A correlation existed between inhibition of liver Δ6 desaturase activity and decreases in edema. 2) The onset of the decrease in edema was time dependent. 3) Selective reduction of arachidonic acid occurred dose dependently in liver, plasma and peritoneal cells. 4) In the presence of SC-26196, controlled refeeding of arachidonic acid, but not oleic acid, reversed the changes resulting from desaturase inhibition. The Δ6 desaturase may be a target for development of antiinflammatory drugs whose mechanism of action is unique.