The enzyme system glucose-6-phosphatase (EC 3.1.3.9) plays a major role in the homeostatic regulation of blood glucose. It is responsible for the formation of endogenous glucose originating from gluconeogenesis and glycogenolysis. Recently, chlorogenic acid was identified as a specific inhibitor of the glucose-6-phosphate translocase component (Gl-6-P translocase) of this enzyme system in microsomes of rat liver. Glucose 6-phosphate hydrolysis was determined in the presence of chlorogenic acid or of new synthesized derivatives in intact rat liver microsomes in order to assess the inhibitory potency of the compounds on the translocase component. Variation in the 3-position of chlorogenic acid had only poor effects on inhibitory potency. Introduction of lipophilic side chain in the 1-position led to 100-fold more potent inhibitors. Functional assays on isolated perfused rat liver with compound 29i, a representative of the more potent derivatives, showed a dose-dependent inhibition of gluconeogenesis and glycogenolyosis, suggesting glucose-6-phosphatase as the locus of interference of the compound for inhibition of hepatic glucose production also in the isolated organ model. Gl-6-P translocase inhibitors may be useful for the reduction of inappropriately high rates of hepatic glucose output often found in non-insulin-dependent diabetes.

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The article contains sections titled: 1. Introduction 2. Physical Properties 3. Chemical Properties 4. Production 5. Analysis 6. Transportation and Storage 7. Toxicology 8. Uses

2-[(2-Pyridylmethyl)sulfinyl]thienoimidazoles were synthesized and investigated as potential inhibitors of gastric H+/K(+)-ATPase. The [3,4-d] isomers of the two possible thienoimidazole series were found to be potent inhibitors of gastric acid secretion in vitro and in vivo. Structure-activity relationships indicate that especially lipophilic alkoxy, benzyloxy, and phenoxy substituents with additional electron-demanding properties in the 4-position of the pyridine moiety combined with an unsubstituted thieno[3,4-d]imidazole lead to highly active compounds with a favorable chemical stability. Various substitution patterns in the thieno[3,4-d]imidazole moiety result in lower biological activity. The heptafluorobutyloxy derivative saviprazole (HOE 731, 5d) was selected for further development and is currently undergoing clinical evaluation. Comprehensive pharmacological studies indicate a pharmacodynamic profile different to omeprazole, the first H+/K(+)-ATPase blocker introduced on the market.

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