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The pharmacological effects of rivoglitazone, a novel thiazolidinedione-derivative peroxisome proliferator–activated receptor (PPAR)-γagonist, were characterized in vitro and in vivo. Rivoglitazone activated human PPARγmore potently compared with rosiglitazone and pioglitazone and had little effect on PPARαand PPARδactivity in luciferase reporter assays. In Zucker diabetic fatty (ZDF) rats, 14-day administration of rivoglitazone decreased the plasma glucose and triglyceride (TG) levels in a dose-dependent manner. The glucose-lowering effect of rivoglitazone was much more potent than those of pioglitazone (ED50: 0.19 vs. 34 mg/kg) and rosiglitazone (ED50: 0.20 vs. 28 mg/kg). In addition, rivoglitazone showed potent antidiabetic effects in diabetic db/dbmice. In Zucker fatty rats, rivoglitazone at a dose of 0.1 mg/kg clearly ameliorated insulin resistance and lowered plasma TG levels by accelerating the clearance of plasma TG. Gene expression analysis in the liver and heart of ZDF rats treated with rivoglitazone for 14 days suggested that rivoglitazone may reduce hepatic glucose production and modulate the balance of the cardiac glucose/fatty acid metabolism in diabetic animals. In summary, we showed that rivoglitazone is a potent and selective PPARγagonist and has a potent glucose-lowering effect via improvement of the insulin resistance in diabetic animal models.