1,3,4-Oxadiazole, 1,3,4-thiadiazole, and 1,2,4-triazole analogs of the fenamates: in vitro inhibition of cyclooxygenase and 5-lipoxygenase activities.
N-Arylanthranilic acids, known generically as the fenamates, are nonsteroidal antiinflammatory drugs (NSAIDs) that block the metabolism of arachidonic acid by the enzyme cyclooxygenase (CO). Substitution of the carboxylic acid functionality of several fenamates with acidic heterocycles provided dual inhibitors of CO and 5-lipoxygenase (5-LO) activities when tested in an intact rat basophilic leukemia (RBL-1) cell line. Compound 5b (IC50 = 0.77 microM (5-LO), 0.27 microM (CO)) which contains an 1,3,4-oxadiazole-2-thione replacement and 10b (IC50 = 0.87 microM (5-LO), 0.85 microM (CO)) which contains a 1,3,4-thiadiazole-2-thione are the most potent inhibitors of 5-LO and CO activities from these series. Both of these heterocyclic analogs of flufenamic acid are also active in carageenin-induced rat footpad edema (CFE), a model of acute inflammation. When dosed orally the ID50s for 5b and 10b in CFE are 8.5 and 4.7 mg/kg, respectively.
Department of Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48106-1047.
D H
DH
Boschelli
D T
DT
Connor
D A
DA
Bornemeier
R D
RD
Dyer
J A
JA
Kennedy
P J
PJ
Kuipers
G C
GC
Okonkwo
D J
DJ
Schrier
C D
CD
Wright
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D004487:Edema / Q000188:drug therapy; D066298:In Vitro Techniques; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000138:chemical synthesis / Q000494:pharmacology; D014230:Triazoles / Q000138:chemical synthesis / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D062367:ortho-Aminobenzoates / Q000138:chemical synthesis* / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D010069:Oxadiazoles; D013830:Thiadiazoles; D014230:Triazoles; D062367:ortho-Aminobenzoates