Novel, selective delta6 or delta5 fatty acid desaturase inhibitors as antiinflammatory agents in mice.
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.
Obukowicz
M G
MG
Discovery Pharmacology, G.D. Searle, St. Louis, Missouri, USA.
Welsch
D J
DJ
Salsgiver
W J
WJ
Martin-Berger
C L
CL
Chinn
K S
KS
Duffin
K L
KL
Raz
A
A
Needleman
P
P
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism / Q000494:pharmacology; D004487:Edema / Q000188:drug therapy; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D044943:Fatty Acid Desaturases / Q000037:antagonists & inhibitors*; D005228:Fatty Acids, Essential / Q000172:deficiency; D005260:Female; D019787:Linoleic Acid / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D005228:Fatty Acids, Essential; D016718:Arachidonic Acid; D019787:Linoleic Acid; D009195:Peroxidase; D044943:Fatty Acid Desaturases