Design, synthesis, and 5-lipoxygenase-inhibiting properties of 1-thio-substituted butadienes.
The synthesis of novel 1-thio-substituted butadienes, designed as mechanism-based 5-lipoxygenase inhibitors, is described. The structure of these compounds closely resembles a proposed high-energy intermediate during the lipoxygenation of arachidonic acid. They demonstrate 5-lipoxygenase inhibition in vitro and in vivo. The most potent compound is 15a with an IC50 of 1.8 microM in vitro. LTC4 release was inhibited by 80% after intraperitoneal administration of 15c at a dose of 2 mg/kg.
Hanko
R
R
Molecular Therapeutics Inc., West Haven, Connecticut 06516.
Hammond
M D
MD
Fruchtmann
R
R
Pfitzner
J
J
Place
G A
GA
D000818:Animals; D001091:Arachidonate Lipoxygenases / Q000037:antagonists & inhibitors*; D001095:Arachidonic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D002070:Butadienes / Q000138:chemical synthesis* / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D016859:Lipoxygenase Inhibitors; D008297:Male; D051379:Mice; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis* / Q000494:pharmacology
D001095:Arachidonic Acids; D002070:Butadienes; D016859:Lipoxygenase Inhibitors; D013438:Sulfhydryl Compounds; C063534:methyl 5-thia-6,8,11,14-eicosatetraenoate; D001091:Arachidonate Lipoxygenases