monofumarate (TAK-438), A Novel and Potent Potassium-Competitive Acid Blocker for the Treatment of Acid-Related Diseases. Authors

Proton pump inhibitors (PPIs) are widely used in the treatment of acid-related diseases. However, several unmetmedical needs, such as suppression of night-time acid secretion and rapid symptom relief, remain. In this study, we investigated the pharmacological effects of 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate (TAK-438), a novel potassium-competitive acid blocker (P-CAB), on gastric acid secretion in comparison with lansoprazole, a typical PPI, and SCH28080 [3-(cyanomethyl)-2-methyl, 8-(phenylmethoxy)imidazo(1,2-a)pyridine], a prototype P-CAB. TAK-438, SCH28080, and lansoprazole inhibited H,K-ATPase activity in porcine gastric microsomes with IC50 values of 0.019, 0.14, and 6.8 mM, respectively, at pH 6.5. The inhibitory activity of TAK-438 was unaffected by ambient pH, whereas the inhibitory activities of SCH28080 and lansoprazole were weaker at pH 7.5. The inhibition by TAK-438 and SCH28080 was reversible and achieved in a K-competitive manner, quite different from that by lansoprazole. TAK-438, at a dose of 4 mg/kg (as the free base), p.o., TABLE 1 IC50 values of TAK-438, SCH28080, and lansoprazole against porcine H ,K-ATPase pH 6.5 pH 7.5 IC50 CI IC50 CI mM TAK-438 0.019 (0.017-0.023) 0.028 (0.023-0.033) SCH28080 0.14 (0.12-0.17) 2.5 (1.6-3.8) Lansoprazole 6.8 (4.6-10) 66 (47-86) Fig. 2C Inhibitory activities of lansoprazole on porcine gastric H,K-ATPase activity. The enzyme was preincubated for 30 min with various concentrations of lansoprazole at pH 6.5 (closed circles) and pH 7.5 (open triangles). Each point represents the mean 6 S.E. of 3 different experiments. completely inhibited basal and 2-deoxy-D-glucose-stimulated gastric acid secretion in rats, and its effect on both was stronger than that of lansoprazole. TAK-438 increased the pH of gastric perfusate to a higher value than did lansoprazole or SCH28080, and the effect of TAK-438 was sustained longer than that of lansoprazole or SCH28080. These results indicate that TAK-438 exerts a more potent and longer-lasting inhibitory action on gastric acid secretion than either lansoprazole or SCH28080. TAK-438 is a novel antisecretory drug that may provide a new option for the patients with acid-related disease that is refractory to, or inadequately controlled by, treatment with PPIs. Results Effect of TAK-438, SCH28080, and Lansoprazole on Gastric H,K-ATPase Activity. The inhibitory effect of TAK-438, SCH28080, and lansoprazole on gastric H,K-ATPase activity is shown in Fig. 2. Under weakly acidic conditions (pH 6.5), all three compounds inhibited gastric H,K-ATPase activity in a concentration-dependent manner. The inhibitory activity of TAK-438 was the most potent. The IC50 values of TAK-438, SCH28080, and lansoprazole were 0.019, 0.14, and 6.8 mM, respectively (Table 1). Under neutral conditions (pH 7.5), the inhibitory activity of TAK-438 was almost the same as that under weakly acidic conditions. On the other hand, the enzyme inhibitory activities of SCH28080 and lansoprazole were weaker under the neutral condition (Table 1).