Abstract

The pharmacological profiles of the novel acid pump antagonist 7-(4-fluorobenzyloxy)-2,3-dimethyl-1-{[(1S,2S)-2-methylcyclopropyl]methyl}-1H-pyrrolo[2,3-d]pyridazine (CS-526) were investigated in terms of hog gastric H⁺,K⁺-ATPase activity, gastric acid secretion, and acute gastroesophageal lesions in comparison with other proton pump inhibitors (PPIs). CS-526 inhibited H⁺,K⁺-ATPase activity in a concentration-dependent manner, with an IC₅₀ value of 61 nM. The inhibitory effect of CS-526 on H⁺,K⁺-ATPase activity was more potent than that of any of the other PPIs examined. The inhibitory mechanism of CS-526 on H⁺,K⁺-ATPase was a competitive antagonism to the K⁺ binding site of H⁺,K⁺-ATPase, and it was also a reversible inhibition. In pylorus-ligated rats, intraduodenal or oral administration of CS-526 inhibited gastric acid secretion in a dose-dependent manner, and the ID₅₀ values were 2.8 or 0.7 mg/kg, respectively. In Heidenhain pouch dogs, intrapouch administration of CS-526 inhibited histamine-stimulated gastric acid secretion in a dose- and retention time-dependent manner. In a reflux esophagitis model, intraduodenal and oral administration of CS-526 prevented esophageal lesions with ID₅₀ values of 5.4 and 1.9 mg/kg, respectively. Lansoprazole prevented esophagitis only by intraduodenal administration (ID₅₀ = 2.2 mg/kg). Furthermore, CS-526 inhibited acute gastric mucosal lesions. These data demonstrate that the novel acid pump antagonist CS-526 has potent antisecretory and antiulcer effects. These findings indicate that CS-526 would have a curative effect on gastroesophageal reflux disease via its potent antisecretory and antiulcer actions.