Pharmacological studies of the new antiinflammatory agent 3-formylamino-7-methylsulfonylamino-6-phenoxy-4'-1-benzopyran-4-o ne. 2nd communication: effect on the arachidonic acid cascades.
The in vitro and in vivo effects of 3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-on e (T-614, CAS 123663-49-0), a new antiinflammatory agent, on arachidonic acid metabolism were investigated in comparison with those of reference drugs. Although the inhibitory effect of T-614 on the synthesis of prostaglandins by rabbit renal microsomes was very weak (IC50 of 58 micrograms/ml), T-614 effectively inhibited the prostaglandin E2 (PGE2) generation by mouse fibroblasts stimulated with bradykinin with an IC50 value of 0.47 micrograms/ml. The suppressive effect of T-614 on the PGE2 generation in fibroblasts was also found when cells were stimulated with Ca ionophore A23187, but not when induced with arachidonic acid. T-614 suppressed the A23187-induced PGE2 generation by rat macrophages, but not the leukotriene B4 production. In addition, 5-lipoxygenase activities in guinea-pig peritoneal exudated cells were not inhibited. In in vivo experiments, at doses of more than 1 mg/kg, T-614 reduced the PGE2 contents in inflammatory exudate of rat carrageenin-sponge type inflammation, but it was almost inactive in inhibiting gastric prostaglandins production up to 100 mg/kg. T-614 also did not affect the urinary PGE2 excretion in rats, and slightly inhibited the thromboxane synthesis in rat blood. Furthermore, the convulsion-induced increase of PGE2 in mouse brain was inhibited by T-614. These data suggest that T-614 inhibits the production of cyclooxgenase-mediated products with apparently different mode from classical non-steroidal antiinflammatory drugs, and may partly explain the discrepancy in pharmacological properties between this compound and other drugs.
Tanaka
K
K
Research Laboratories, Toyama Chemical Co., Ltd., Japan.
Makino
S
S
Shimotori
T
T
Aikawa
Y
Y
Inaba
T
T
Yoshida
C
C
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism*; D001578:Benzopyrans / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis / Q000652:urine; D005122:Exudates and Transudates / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005753:Gastric Mucosa / Q000378:metabolism; D006168:Guinea Pigs; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D066298:In Vitro Techniques; D007679:Kidney Medulla / Q000187:drug effects / Q000378:metabolism; D007975:Leukotriene B4 / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001578:Benzopyrans; D006893:Hydroxyeicosatetraenoic Acids; D013449:Sulfonamides; C077313:T 614; D007975:Leukotriene B4; D016718:Arachidonic Acid; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; D015232:Dinoprostone