AUTHOR=Lu Ming , Cui Yi , Li Nailin , He Yan , Zhou Ling , Xiu Jin , Hu Pingsheng 

TITLE=Pharmacological characterization of linaprazan glurate (X842), a novel potassium-competitive acid blocker, in vitro and in vivo

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1636523

DOI=10.3389/fphar.2025.1636523

ISSN=1663-9812

ABSTRACT=IntroductionThe 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.MethodsPharmacokinetic profiling, hydrogen (H+)/potassium (K+)-ATPase inhibition, and gastric acid inhibition experiments were performed.ResultsX842 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.DiscussionX842 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.