Effect of the oral absorption of benzenesulfonanilide-type cyclooxygenase-1 inhibitors on analgesic action and gastric ulcer formation
✍ Scribed by Xiaoxia Zheng; Hiroyuki Oda; Shun Harada; Yukio Sugimoto; Akihiro Tai; Kenji Sasaki; Hiroki Kakuta
- Publisher
- John Wiley and Sons
- Year
- 2008
- Tongue
- English
- Weight
- 129 KB
- Volume
- 97
- Category
- Article
- ISSN
- 0022-3549
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✦ Synopsis
A benzensulfonanilide-type cyclooxygenase-1 (COX-1)-selective inhibitor, ZXX2-77: 4-amino-4 0 -chloro-N-methylbenzenesulfonanilide (4a), has been reported as a novel analgesic that does not cause gastric damage. This compound has a weak analgesic effect but has potent in vitro COX-1 inhibitory activity. Since the reason for the weak analgesic effect in vivo was thought to be the low rate of oral absorption, the blood concentration of ZXX2-77 (4a) was measured in rats. It was found that the C max value (1.2 mM) of ZXX2-77 (4a) at a dose of 30 mg/kg did not reach the COX-1 IC 50 value (3.2 mM). On the other hand, ZXX2-79 (4b) (SO 2 NH derivative of ZXX2-77 (4a); 4-amino-4 0chlorobenzenesulfonanilide), which shows less potent COX inhibitory activities (COX-1 IC 50 ¼ 12 mM, COX-2 IC 50 ¼ 150 mM) than those of ZXX2-77 (4a) in vitro, was found to be more absorbable (C max ¼ 16 mM at a dose of 30 mg/kg in rats) than ZXX2-77 (4a). Furthermore, ZXX2-79 (4b) not only showed a potent analgesic effect in a formalin test but also caused little gastric damage. These findings indicate that demethylated sulfonamide compounds are more easily absorbed than are N-methylated sulfonamide compounds and suggest that COX-1-selective inhibitors will be useful as analgesics that do not cause gastric damage.