ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Gastrointestinal and Hepatic Pharmacology
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1636523
This article is part of the Research TopicAdvances in the Potential Treatments of Gastrointestinal and Liver Diseases: Addressing the Public Health Burden, Volume IIView all 7 articles
Pharmacological characterization of linaprazan glurate (X842), a novel potassium-competitive acid blocker, in vitro and in vivo
Provisionally accepted
- 1Sinorda Pharmaceuticals Ltd, Gui Yang, China
- 2Affiliated Hospital of Guizhou Medical University, Guiyang, China
- 3Karolinska Institutet, Stockholm, Sweden
- 4The Affiliated Hospital of Guizhou Medical University, Guiyang, China
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Introduction: The aim of this study is to characterize the pharmacology of linaprazan glurate (X842), an ethyl ester prodrug of linaprazan (a novel potassium-competitive acid blocker), in animal species in vitro and in vivo to achieve a better pharmacological profile. Methods: Pharmacokinetic profiling, hydrogen (H+)/potassium (K+)-ATPase inhibition, and gastric acid inhibition experiments were performed. Results: X842 was rapidly absorbed with a very low plasma concentration. X842 was rapidly transformed by enzymatic cleavage into its active metabolite, linaprazan, as shown by the half-life, maximum concentration, and area under the concentration–time curve of the two substances. Selective inhibition of the gastric H+/K+-ATPase and acid formation in vitro was observed. Linaprazan, X842, and vonoprazan selectively inhibited acid formation from gastric H+/K+-ATPase in a potassium-dependent manner. The inhibitory potency rank was vonoprazan > linaprazan > X842, with half-maximal inhibitory concentration(IC50) values of 17, 40, and 436 nM, respectively, showing that X842 is a very weak inhibitor of H+/K+-ATPase in vitro. In a pylorus-ligated rat model, X842 potently inhibited gastric acid secretion in a dose-dependent manner with a long duration of action, highlighting the two stages of pharmacokinetics that give the compound both its fast onset and its long-lasting duration of action on H+/K+-ATPase. Discussion: X842 is a prodrug that exerts pharmacological effects both independently and through its metabolized active compound linaprazan, with both a fast onset and a long duration of action. X842 could be a potential drug candidate worthy of further clinical study.
Keywords: Acid blocker, ATPase, competitive, Gastric Acid, Potassium
Received: 28 May 2025; Accepted: 25 Aug 2025.
Copyright: © 2025 Lu, Cui, Li, He, Zhou, Xiu and Hu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Pingsheng Hu, Sinorda Pharmaceuticals Ltd, Gui Yang, China
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