The binding selectivity of vonoprazan ( TAK ‐438) to the gastric H + ,K + ‐ ATP ase

Summary Background The gastric H + ,K + ‐ ATP ase is the preferred target for acid suppression. Until recently, the only drugs that effectively inhibited this ATP ase were the proton pump inhibitors ( PPI s). PPI s are acid‐activated prodrugs that require acid protection. Once acid‐activated, PPI s bind to cysteines of the ATP ase, resulting in covalent, long‐lasting inhibition. The short plasma half‐life of PPI s and continual de novo synthesis of the H + ,K + ‐ ATP ase result in difficulty controlling night‐time acid secretion. A new alternative to PPI s is the pyrrolo‐pyridine, vonoprazan ( TAK ‐438), a potassium‐competitive acid blocker ( PCAB ) that does not require acid protection. In contrast to other PCAB s, vonoprazan has a long duration of action, resulting in 24‐h control of acid secretion, a high pK a of 9.37 and high affinity ( K i = 3.0 ηmol/L). Aim To determine binding selectivity of vonoprazan for the gastric H + ,K + ‐ ATP ase and to explain its slow dissociation. Methods Gastric gland and parietal cell binding of vonoprazan was determined radiometrically. Molecular modelling explained the slow dissociation of vonoprazan from the H + ,K + ‐ ATP ase. Results Vonoprazan binds selectively to the parietal cell, independent of acid secretion. Vonoprazan binds in a luminal vestibule between the surfaces of membrane helices 4, 5 and 6. Exit of the drug to the lumen is hindered by asp137 and asn138 in the loop between TM 1 and TM 2, which presents an electrostatic barrier to movement of the sulfonyl group of vonoprazan. This may explain its slow dissociation from the H + ,K + ‐ ATP ase and long‐lasting inhibition. Conclusion The binding model provides a template for design of novel potassium‐competitive acid blockers.