[Pharmacological characteristics and clinical efficacies of a novel potassium-competitive acid blocker, vonoprazan fumarate].

Proton pump inhibitors (PPIs) inhibit H+, K+-ATPase, an enzyme which is the final step of gastric acid secretion and is selectively located in the gastric parietal cells. PPIs block the enzyme in a covalent and irreversible binding manner, thus providing better efficacy than previous pharmacological agents such as antacids and histamine H2 receptor antagonists. Although PPIs have been the first-line therapeutic option for acid related diseases (ARDs), there are several limitations to their efficacy, i.e. short half-life in blood, insufficient acid suppression especially at night, necessity of repeated dosages for full action, and large variation in efficacy among patients due to CYP2C19 polymorphism. To overcome these shortcomings, we performed a high-throughput random screening using in-house chemical libraries and further lead optimization to look for the most relevant clinical candidate compounds. As the results of these researches, we discovered vonoprazan fumarate, a novel gastric acid antisecretory agent which inhibits H+, K+-ATPase in a reversible and K+-competitive manner. Vonoprazan exerted a more potent and longer lasting inhibitory effect than lansoprazole on gastric acid secretion in preclinical studies, presumably by its high accumulation profile in the gastric parietal cells. It also exhibited a rapid onset of action and prolonged inhibition of intragastric acidity in humans and showed remarkable effects on multiple ARDs including erosive esophagitis and Helicobacter pylori eradication. Vonoprazan fumarate was approved in 2014 for clinical use in Japan. Vonoprazan is a new therapeutic option which can potentially improve outcomes compared with conventional PPI-based treatments for ARDs.

Discovery, synthesis, and structure-activity relations of 3,4-dihydro-1H-spiro(naphthalene-2,2'-piperidin)-1-ones as potassium-competitive acid blockers.

With the aim to discover a gastric antisecretory agent more potent than the existing proton pump inhibitors, novel 3,4-dihydro-1H-spiro(naphthalene-2,2'-piperidin)-1-one derivatives, which could occupy two important lipophilic pockets (described as LP-1 and LP-2) of H+,K+-ATPase and can strongly bind to the K+-binding site, were designed based on a docking model. Among the compounds synthesized, compound 4d showed a strong H+,K+-ATPase-inhibitory activity and a high stomach concentration in rats, resulting in potent inhibitory action on histamine-stimulated gastric acid secretion in rats. Furthermore, 4d exerted significant inhibitory action on histamine-stimulated gastric-acid secretion in rats with a rapid onset and moderate duration of action after the administration. These findings may lead to a new insight into the drug design of potassium-competitive acid blockers.