1,3,4-OXADIAZOLE, 1,3,4-THIADIAZOLE, AND 1,2,4-TRIAZOLE ANALOGS OF THE FENAMATES - IN-VITRO INHIBITION OF CYCLOOXYGENASE AND 5-LIPOXYGENASEACTIVITIES

N-Arylanthranilic acids, known generically as the fenamates, are nonst eroidal antiinflammatory drugs (NSAIDs) that block the metabolism of a rachidonic acid by the enzyme cyclooxygenase (CO). Substitution of the carboxylic acid functionality of several fenamates with acidic hetero cycles provided dual inhibitors of CO and 5-lipoxygenase (5-LO) activi ties when tested in an intact rat basophilic leukemia (RBL-1) cell lin e. Compound 5b (IC50 = 0.77 muM (5-LO), 0.27 muM (CO)) which contains an 1,3,4-oxadiazole-2-thione replacement and 10b (IC50 = 0.87 muM (5-L O), 0.85 muM (CO)) which contains a 1,3,4-thiadiazole-2-thione are the most potent inhibitors of 5-LO and CO activities from these series. B oth of these heterocyclic analogs of flufenamic acid are also active i n carageenin-induced rat footpad edema (CFE), a model of acute inflamm ation. When dosed orally the ID50s for 5b and 10b in CFE are 8.5 and 4 .7 mg/kg, respectively.