Distribution- and metabolism-based drug discovery: SAR and SMR exploration of alkoxy-substituted vonoprazan derivatives as new potassium-competitive acid blockers.

Building on the distribution- and metabolism-based drug design (DMBDD) strategy, SH-337 was previously identified as a promising potassium-competitive acid blocker candidate for treating acid-related diseases. To explore the balance between efficacy and safety for this novel chemotype, we designed and synthesized a series of alkoxy-substituted vonoprazan derivatives. Specifically, alkoxy substitutions such as cycloalkyl and oxygen-containing heterocycles were found to modulate metabolic stability by optimizing steric hindrance and lipophilicity, thereby balancing efficacy and systemic exposure. Comprehensive structure-activity relationship (SAR) and structure-metabolism relationship (SMR) studies led to the identification of a new lead compound, 16d. It displayed strong potency, favorable physicochemical properties, and a moderate metabolic rate in human liver microsomes that was positioned between SH-337 and vonoprazan. Notably, 16d exhibited high stomach-specific distribution with rapid and sustained accumulation in stomach tissue, resulting in low systemic and hepatic exposure, which may contribute to an improved safety profile. Moreover, 16d exhibited comparable in vivo efficacy to that of both vonoprazan and SH-337 in histamine-induced and 2-DG-induced gastric acid secretion rat models. These positive results further validate the effectiveness and feasibility of the DMBDD strategy, and the analogs developed by modulating metabolic stability are promising candidates for future clinical trials.