1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine Monofumarate (TAK-438), a Novel and Potent Potassium-Competitive Acid Blocker for the Treatment of Acid-Related Diseases

Abstract

Proton pump inhibitors (PPIs) are widely used in the treatment of acid-related diseases. However, several unmet medical 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 of P-CAB. TAK-438, SCH28080, and lansoprazole inhibited H ϩ ,K ϩ -ATPase activity in porcine gastric microsomes with IC 50 values of 0.019, 0.14, and 7.6 M, 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 ϩ -competitive manner, quite different from that by lansoprazole. TAK-438, at a dose of 4 mg/kg (as the free base) orally, 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.

Effect of Therapeutic and Supratherapeutic Doses of Vonoprazan on the QT/QTc Interval in a Phase I Randomized Study in Healthy Subjects

“…Potassium‐competitive acid blockers (P‐CABs) represent a novel class of acid‐suppressing agents that are a potential alternative to proton pump inhibitors (PPIs) for the treatment of gastroesophageal reflux disease 1. In contrast to PPIs, P‐CABs are acid‐stable H+, K+‐ATPase inhibitors that inhibit H+, K+‐ATPase noncovalently in a K+‐competitive manner 2…”

Gastric Mucosal Atrophy Might Be Associated with the Efficacy of First-Line Therapy Using Vonoprazan for <i>Helicobacter pylori</i>

“…The acid-inhibitory effect of VPZ was greater than that of the PPIs [11] [12] [32]. The CYP2C19 genotype was shown to influence the inhibitory effects of PPIs on gastric acids [31].…”

“…Vonoprazan (VPZ) is a novel orally administered member of this class. VPZ has a potent and long-lasting anti-secretory effect on hydrogen/potassium-ATPase because of its high level of accumulation and slow clearance from gastric tissue [11] [12]. The acid-inhibitory effects of VPZ are much more potent than those of PPIs; therefore, it can be expected to be more effective when used for H. pylori eradication.…”

“…Similar to PPIs, P-CABs inhibit gastric hydrogen/potassiumATPase but, unlike PPIs, P-CABs inhibit the enzyme in a potassium-competitive and reversible manner [11]. Vonoprazan (VPZ) is a novel orally administered member of this class.…”

The first-line regimens of Helicobacter pylori eradication in Korea

“…P-CABs inhibit gastric hydrogen/potassium-ATPase in a potassium-competitive and reversible manner [17]. Because P-CAB is highly accumulated and slowly excreted from gastric tissue, it has a potent and a long-lasting anti-secretory effect on gastric acid [18]. In Japan, triple therapy based on vonoprazan, a novel P-CAB, showed favored eradication rate compared to lansoprazole-based triple therapy [19].…”