Discovery and development of a new insulin sensitizing agent, pioglitazone

Abstract

Insulin resistance is a characteristic feature of type II diabetes as well as obesity. This insulin resistant state at the peripheral tissue level causes impaired glucose utilization, leading to hyperglycemia. Studies of antidiabetic agents by Takeda originated more than three decades ago when KK mice were introduced, followed by the development of a highly insulin-resistant animal model, KKAy mice. The first 2,4-thiazolidinedione derivative AL-321, which exhibited hypoglycemic effects in KKAy mice, was discovered by modification of the hypolipidemic agent AL-294 as a lead compound. Extensive structure-activity relationship studies on the analogues of AL-321 led to the selection of ciglitazone (ADD-3878) as a candidate for clinical evaluation. Ciglitazone, a prototypical compound in the series, was shown to normalize hyperglycemia, hyperinsulinemia, and hypertriglyceridemia in various insulin-resistant animal models without altering normoglycemia in nondiabetic animal models. However, it appeared that a more potent compound was needed for further clinical evaluation of this class of compound. Further study of this series of compounds led to the finding of pioglitazone (AD-4833) as a promising clinical candidate. Pioglitazone clearly ameliorates the abnormal glucose and lipid metabolism in diabetic patients and was marketed in the USA in August 1999 for the treatment of type II diabetes. Pioglitazone is now marketed in more than 40 countries world wide. Historical aspects of our studies on pioglitazone and its biological activities are described.