Acc Inhibitors In Longterm Efficacy Studies

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Despite the relatively large number of publications in the area of ACC inhibition, there have been few disclosures reporting the effects of long-term administration of ACC inhibitors on metabolic syndrome-related endpoints. Recently, two disclosures reported the results of studies of the balanced ACC1/ACC2 inhibitor 2 in mouse models of metabolic syndrome [48,49]. In the first study, 2 was administered in chow to ob/ob mice at doses of 50 and 100 mg/kg for 8 weeks. Treatment with 2 resulted in increased glucose and triglyceride levels and decreased insulin levels in blood. The AUC and peak glucose response in an oral glucose tolerance test (OGTT) were also increased. After 6 weeks, the 100 mg/kg dose group was lowered to 20 mg/kg. This resulted in normalization of triglyceride and glucose levels, but insulin levels remained low. Body weight decreased in the 100 mg/kg dosing group, but food intake remained approximately the same for all the animals in the study. It was concluded that 2 worsened the diabetic phenotype in ob/ob mice, but the authors indicated that the origin of this effect was unclear [48].

The second study with 2 was performed in diet-induced obese (DIO) C57Bl6/J mice. Compared to control DIO mice, mice treated with 2 showed significantly less weight gain over the course of the 6-week study. However, mice treated with 2 had liver triglyceride and total cholesterol levels that were identical to untreated DIO mice. In a glucose infusion clamp study, the glucose infusion rate was slightly higher for the treated animals (~10%) than for the untreated DIO mice. The study concluded that treatment with 2 had a moderate effect on improving the diabetic phenotype of DIO mice [49].

In addition to these studies with 2, the effects of the dual ACC1/ ACC2 inhibitor 1 in in vivo efficacy studies in high-fat-fed C57Bl6/J mice have been reported [50]. In mice fed a high-fat chow diet, 1 administered in-diet (50 and 100 mg/kg/day) dose-dependently reduced body weight gain relative to a high-fat chow-fed control group. Mice treated with 1 also had significantly higher levels of p-hydroxybutyrate than the high-fat-fed control group, indicating a shift in energy utilization to increased fatty acid metabolism in these mice. Additionally, fasting plasma insulin levels were lower in mice treated with 1 than in the high-fat control group, and in a glucose infusion rate study, mice dosed with 1 showed an improved response relative to the high-fat mice. Interestingly, the level of hepatic malonyl-CoA was found to be lower in the group dosed with 50 mg/kg of 1 than it was in the animals that were fed normal chow, while animals receiving 100 mg/kg of 1 had identical malonyl-CoA levels to the animals fed normal chow. The study concluded that treatment with 1 resulted in favorable effects on diabetic symptoms in DIO mice.

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