Effect of the oral absorption of benzenesulfonanilide-type cyclooxygenase-1 inhibitors on analgesic action and gastric ulcer formation

A benzensulfonanilide-type cyclooxygenase-1 (COX-1)-selective inhibitor, ZXX2-77: 4-amino-4′-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 μM) of ZXX2-77 (4a) at a dose of 30 mg/kg did not reach the COX-1 IC₅₀ value (3.2 μM). On the other hand, ZXX2-79 (4b) (SO₂NH derivative of ZXX2-77 (4a); 4-amino-4′-chlorobenzenesulfonanilide), which shows less potent COX inhibitory activities (COX-1 IC₅₀ = 12 μM, COX-2 IC₅₀ = 150 μM) than those of ZXX2-77 (4a) in vitro, was found to be more absorbable (C_max = 16 μM 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.