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Vol. 287, Issue 1, 157-166, October 1998

Novel, Selective Delta 6 or Delta 5 Fatty Acid Desaturase Inhibitors as Antiinflammatory Agents in Mice

Mark G. Obukowicz, Dean J. Welsch, William J. Salsgiver, Cynthia L. Martin-Berger, Kevin S. Chinn, Kevin L. Duffin, Amiram Raz and Philip Needleman

Discovery Pharmacology (M.G.O., K.S.C., P.N.), Protein Biochemistry and Molecular Biology (D.J.W., W.J.S.), and Cardiovascular Diseases Research (C.L.M.-B.), G.D. Searle, St. Louis, Missouri and Monsanto Corporate Research (K.L.D.), St. Louis, Missouri and Department of Biochemistry (A.R.), Tel Aviv University, Tel Aviv, Israel

Decreased synthesis of arachidonic acid by inhibition of the Delta 6 or Delta 5 desaturase was evaluated as a means to mitigate inflammation. Using quantitative in vitro and in vivo radioassays, novel compounds representing five classes of Delta 5 desaturase inhibitors and one class of Delta 6 desaturase inhibitor were identified. The Delta 6 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 Delta 6 desaturase inhibitor: 1) A correlation existed between inhibition of liver Delta 6 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 Delta 6 desaturase may be a target for development of antiinflammatory drugs whose mechanism of action is unique.

0022-3565/98/2871-0157$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics


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