EFFECTS OF NOVEL ANTIINFLAMMATORY COMPOUNDS ON HEALING OF ACETIC ACID-INDUCED GASTRIC-ULCER IN RATS

Nonsteroidal anti-inflammatory drugs often cause development of signif icant GI lesions. Selective inhibitors of prostaglandin G/H synthase/c yclooxygenase-2 (PGHS-2) enzyme and some dual inhibitors of PGHS/5-lip oxygenase (5-LO) enzymes have been reported to be potent anti-inflamma tory compounds that carry a much lower risk of having GI irritating ef fects. We have evaluated the anti-inflammatory effect and the GI safet y profile of three new anti-inflammatory compounds: the selective PGHS -2 inhibitors NS-398 and PD 138387 and the PGHS/5-LO dual inhibitor PD 137968. All the compounds tested showed an anti-inflammatory activity in the carragenan footpad edema test in rats. None of these compounds caused either gastric damage 4 h after p.o. administration of 100 mg/ kg in rats or inhibition of PGE(2) synthesis in the stomach. However, when administered p.o. at an effective anti-inflammatory dose to rats with pre-existing acetic acid-induced gastric ulcer, NS-398 caused a s tatistically significant delay of ulcer healing. No impairment of the ulcer healing was observed with the other compounds evaluated. Derivat ives of 2,6-di-tert-butylphenol, whose members may act as PGHS-1/PGHS- 2 inhibitors, selective PGHS-2 inhibitors or PGHS/5-LO dual inhibitors , are novel anti-inflammatory compounds that are devoid of GI irritati ng effects and do not affect the rate of pre-existing gastric ulcer he aling.