No abstract

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.

The glucose-6-phosphatase (G-6- Pase) system catalyzes the terminal enzymatic step of gluconeogenesis and glycogenolysis. Inhibition of the G-6- Pase system in the liver is expected to result in a reduction of hepatic glucose production irrespective of the relative contribution of gluconeogenesis or glycogenolysis to hepatic glucose output. In isolated perfused rat liver, S-3483, a derivative of chlorogenic acid, produced concentration-dependent inhibition of gluconeogenesis and glycogenolysis in a similar concentration range. In fed rats, glucagon-induced glycogenolysis resulted in hyperglycemia for nearly 2 h. Intravenous infusion of 50 mg ⋅ kg−1 ⋅ h−1S-3483 prevented the hyperglycemic peak and subsequently caused a further lowering of blood glucose. In 24-h starved rats, in which normoglycemia is maintained predominantly by gluconeogenesis, intravenous infusion of S-3483 resulted in a constant reduction of blood glucose levels. Intrahepatic concentrations of glucose-6-phosphate (G-6- P) and glycogen were significantly increased at the end of both in vivo studies. In contrast, lowering of blood glucose in starved rats by 3-mercaptopicolinic acid was accompanied by a reduction of G-6- P and glycogen. Our results demonstrate for the first time in vivo a pharmacologically induced suppression of hepatic G-6- P activity with subsequent changes in blood glucose levels.

The voltage-gated potassium channel Kv1.5 is regarded as a promising target for the development of new atrial selective drugs with fewer side effects. In the present study the discovery of ortho,ortho-disubstituted bisaryl compounds as blockers of the Kv1.5 channel is presented. Several compounds of this new class were synthesized and screened for their ability to block Kv1.5 channels expressed in Xenopus oocytes. The observed structure-activity relationship (SAR) is described by a pharmacophore model that consists of three hydrophobic centers in a triangular arrangement. The hydrophobic centers are matched by a phenyl or pyridyl ring of the bisaryl core and both ends of the side chains. The most potent compounds (e.g., 17c and 17o) inhibited the Kv1.5 channel with sub-micromolar half-blocking concentrations and displayed 3-fold selectivity over Kv1.3 and no significant effect on the HERG channel and sodium currents. In addition, compounds 17c and 17m have already shown antiarrhythmic effects in a pig model.

No abstract