Substituted thieno[3,4-d]imidazoles, a novel group of H+/K(+)-ATPase inhibitors. Differentiation of their inhibition characteristics from those of omeprazole.

The action of the H+/K(+)-ATPase inhibitors, Hoe 731 and S 4216, both thieno-imidazole derivatives, was compared with that of the benzimidazole derivative, omeprazole. In intact, gastric membrane vesicles under conditions shown to result in acidification of the vesicle interior. Hoe 731 and S 4216 inhibited H+/K(+)-ATPase activity with an IC50 value of about 1.0 microM. In the absence of a generated pH gradient the respective IC50 values were 5.5 and 2.1 microM. In contrast, omeprazole inhibited the enzyme only in the presence of proton accumulation (IC50: 0.7 microM). The inhibitory action of omeprazole on H+/K(+)-ATPase-mediated proton transport was prevented by the membrane permeable mercaptane, dithioerythritol, but not by the membrane impermeable, mercaptane glutathione, whereas both mercaptanes were able to prevent the effect of Hoe 731 and S 4216. These results indicate that the thienoimidazoles react with intravesicular (luminal) and extravesicular (cytosolic) SH groups of the H+/K(+)-ATPase, whereas omeprazole interacts uniquely with luminal SH groups of the enzyme. In isolated parietal cells all drugs caused a concentration-dependent inhibition of HCl production, as measured by [14C]aminopyrine uptake, during histamine and dibutyryl-cAMP stimulation. The IC50 value was 0.1 microM for Hoe 731 and omeprazole and 0.4 microM for S 4216 after 30-min incubation. The inhibitory action of Hoe 731 and S 4216 faded with increasing incubation time, whereas omeprazole caused an unchanged inhibition over the entire 120-min incubation period. We suggest that several factors, e.g. weaker chemical stability of the drugs or perturbation of cellular glutathione levels, may be responsible for the fading inhibitory action of thienoimidazoles in the parietal cell.