Lesch C A, Gilbertsen R B, Song Y, Dyer R D, Schrier D, Kraus E R, Sanchez B, Guglietta A
Parke-Davis Pharmaceutical Research Division, Warner-Lambert Co., Ann Arbor, Michigan, USA.
J Pharmacol Exp Ther. 1998 Oct;287(1):301-6.
Nonsteroidal anti-inflammatory drugs often cause development of significant GI lesions. Selective inhibitors of prostaglandin G/H synthase/cyclooxygenase-2 (PGHS-2) enzyme and some dual inhibitors of PGHS/5-lipoxygenase (5-LO) enzymes have been reported to be potent anti-inflammatory compounds that carry a much lower risk of having GI irritating effects. We have evaluated the anti-inflammatory effect and the GI safety 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 PGE2 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 statistically significant delay of ulcer healing. No impairment of the ulcer healing was observed with the other compounds evaluated. Derivatives 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 irritating effects and do not affect the rate of pre-existing gastric ulcer healing.
非甾体抗炎药常导致严重胃肠道病变的发生。据报道，前列腺素G/H合酶/环氧化酶-2（PGHS-2）的选择性抑制剂以及一些PGHS/5-脂氧合酶（5-LO）的双重抑制剂是强效抗炎化合物，其胃肠道刺激作用风险要低得多。我们评估了三种新型抗炎化合物的抗炎作用和胃肠道安全性：选择性PGHS-2抑制剂NS-398和PD 138387以及PGHS/5-LO双重抑制剂PD 137968。所有测试化合物在大鼠角叉菜胶足垫水肿试验中均显示出抗炎活性。这些化合物在大鼠口服100 mg/kg 4小时后均未引起胃损伤，也未抑制胃中PGE2的合成。然而，当以有效抗炎剂量口服给予已存在乙酸诱导胃溃疡的大鼠时，NS-398导致溃疡愈合在统计学上显著延迟。评估的其他化合物未观察到溃疡愈合受损。2,6-二叔丁基苯酚的衍生物，其成员可能作为PGHS-1/PGHS-2抑制剂、选择性PGHS-2抑制剂或PGHS/5-LO双重抑制剂，是新型抗炎化合物，无胃肠道刺激作用，且不影响已存在的胃溃疡愈合速度。
