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, suchas suppression of night-time acid secretion and rapid symptom relief, remain. In this study, we investigated the pharmacologicaleffects of 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate (TAK-438), a novelpotassium-competitive acid blocker (P-CAB), on gastric acid secretion in comparison with lansoprazole, a typical PPI, andSCH28080 [3-(cyanomethyl)-2-methyl, 8-(phenylmethoxy)imidazo(1,2-a)pyridine], a prototype P-CAB. TAK-438, SCH28080, andlansoprazole 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 ofSCH28080 and lansoprazole were weaker at pH 7.5. The inhibition by TAK-438 and SCH28080 was reversible and achieved in aK-competitive manner, quite different from that by lansoprazole. TAK-438, at a dose of 4 mg/kg (as the free base), p.o.,TABLE 1IC50 values of TAK-438, SCH28080, and lansoprazole against porcine H,K-ATPasepH 6.5pH 7.5IC50CIIC50CImMTAK-4380.019(0.017-0.023)0.028(0.023-0.033)SCH280800.14(0.12-0.17)2.5(1.6-3.8)Lansoprazole6.8(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 variousconcentrations 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 strongerthan 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-438exerts a more potent and longer-lasting inhibitory action on gastric acid secretion than either lansoprazole or SCH28080. TAK-438 is anovel antisecretory drug that may provide a new option for the patients with acid-related disease that is refractory to, or inadequatelycontrolled by, treatment with PPIs. ResultsEffect of TAK-438, SCH28080, and Lansoprazole on Gastric H,K-ATPase Activity. The inhibitory effect of TAK-438,SCH28080, and lansoprazole on gastricH,K-ATPase activity is shown in Fig. 2. Under weakly acidic conditions (pH 6.5), allthree compounds inhibited gastricH,K-ATPase activity in a concentration-dependent manner. The inhibitory activity ofTAK-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 thatunder weakly acidic conditions. On the other hand, the enzyme inhibitory activities of SCH28080 and lansoprazole wereweaker under the neutral condition (Table 1).