Obukowicz M G, Welsch D J, Salsgiver W J, Martin-Berger C L, Chinn K S, Duffin K L, Raz A, Needleman P
Discovery Pharmacology, G.D. Searle, St. Louis, Missouri, USA.
J Pharmacol Exp Ther. 1998 Oct;287(1):157-66.
Decreased synthesis of arachidonic acid by inhibition of the Delta6 or Delta5 desaturase was evaluated as a means to mitigate inflammation. Using quantitative in vitro and in vivo radioassays, novel compounds representing five classes of Delta5 desaturase inhibitors and one class of Delta6 desaturase inhibitor were identified. The Delta6 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 Delta6 desaturase inhibitor: 1) A correlation existed between inhibition of liver Delta6 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 Delta6 desaturase may be a target for development of antiinflammatory drugs whose mechanism of action is unique.
通过抑制Δ6或Δ5去饱和酶来减少花生四烯酸的合成，以此作为减轻炎症的一种手段进行了评估。利用定量体外和体内放射性测定法，鉴定出了代表五类Δ5去饱和酶抑制剂和一类Δ6去饱和酶抑制剂的新型化合物。Δ6去饱和酶抑制剂SC-26196在小鼠体内具有药代动力学和药效学特征，这使得评估去饱和酶活性的慢性抑制的药理作用成为可能。在小鼠角叉菜胶足肿胀模型中，SC-26196减轻水肿的程度与吲哚美辛或必需脂肪酸缺乏相同。SC-26196的抗炎特性与其作为Δ6去饱和酶抑制剂的作用机制一致：1）肝脏Δ6去饱和酶活性的抑制与水肿减轻之间存在相关性。2）水肿减轻的开始具有时间依赖性。3）花生四烯酸在肝脏、血浆和腹膜细胞中呈剂量依赖性地选择性减少。4）在存在SC-26196的情况下，控制补充花生四烯酸而非油酸可逆转去饱和酶抑制导致的变化。Δ6去饱和酶可能是开发作用机制独特的抗炎药物的靶点。
