Discovery of novel benzimidazole derivatives as potent potassium-competitive acid blockers for the treatment of acid-related diseases.

[Display omitted] • Thirty benzimidazole derivatives were designed and synthesized as novel potassium-competitive acid blockers (P-CABs). • A12 and A18 efficiently inhibited H+, K+-ATPase activity. • A12 and A18 significantly inhibited gastric acid secretion of SD rats in vivo. • A12 and A18 showed satisfactory drug stability and pharmacokinetic properties. H+, K+-ATPase, as the most critical enzyme in gastric acid secretion, has long been an attractive target for the treatment of acid-related diseases. In this study, a series of benzimidazole derivatives were designed and synthesized through conformational restriction and skeleton hopping strategies by using vonoprazan as the lead compound. Among them, compounds A12 (IC 50 = 9.32 μM) and A18 (IC 50 = 5.83 μM) showed better inhibition at the enzyme level. In addition, gastric acid secretion inhibition was assessed in vivo , and the results showed that A12 and A18 significantly inhibited basal gastric acid secretion, 2-deoxy- d -glucose (2DG) stimulated gastric acid secretion and histamine-stimulated gastric acid secretion. In further in vitro metabolic experiments, A12 and A18 demonstrated excellent stability and low toxicity. Pharmacokinetic studies showed that the p.o. and i.v. half-lives of A18 were 3.21 h and 8.67 ± 1.15 h, respectively. In summary, A18 might be a novel and effective potassium-competitive acid blocker, and this study provides strong support for it use in the treatment of acid-related diseases. [ABSTRACT FROM AUTHOR]