To find new H+/K+‐ATPase inhibitors for the treatment of peptic ulcer disease, a series of novel N‐aryl isothiourea derivatives were synthesized and their structures were identified by 1H NMR and GC‐MS. The effects of these compounds on inhibiting gastric acid secretion were evaluated by the guinea pig stomach mucous membrane study with pantoprazole magnesium as a positive control. The results showed that, of the 37 N‐aryl isothiourea compounds synthesized, 20 compounds have comparable or stronger gastric acid inhibitory activities than that of pantoprazole magnesium. The quantitative structure–activity relationships (QSARs) of the N‐aryl isothiourea compounds were also studied by comparative molecular field analysis (CoMFA) computation, and the model structure that was supposed to give more powerful bioactivities was finally predicted.