Pioglitazone Actos

Structural Formula

Ball-and-Stick Model

Structural Formula

N O

= Carbon = Hydrogen A = Oxygen A = Nitrogen = Sulfur

Year of discovery: ca. 1990 by Takeda, Japan; Year of introduction: 1999 (Takeda & Ell Lilly); Drug category Peroxisome proliferator-activated receptor-y (PPARy) activator/thiazolidinedione class of insulin sensitizers; Main uses: For treatment of type 2 diabetes; Related drugs: Rosiglitazone (Avandia, SKB).

Insulin resistance and elevated blood glucose predispose to type 2 diabetes and cardiovascular disease even when insulin levels are normal. A class of drugs known as thiazolidinediones was long known also to reduce blood glucose levels. However, these early agents generally were found to cause serious liver toxicity. Indeed, the first thiazolidinedione to be approved for human use in the US (troglitazone) had to be withdrawn from the market because it caused life-threatening liver damage in a tiny subset of patients. It was not until recently that safer thiazolidinediones were developed. Pioglita-zone hydrochloride was approved in 1999 specifically for the treatment of type 2 diabetes and it is sold as Actos.1 Rosiglitazone, another approved thiazolidinedione, is marketed as Avandia.

Rosiglitazone (Avandia

Rosiglitazone (Avandia

Pioglitazone is a highly selective and potent activator (agonist) for peroxisome proliferator-activated receptor-y (PPARy). PPARs are found in skeletal muscle and liver tissues that are the targets for insulin action. PPARs are ligand-activated transcription factors that belong to the nuclear hormone receptor family and are activated by dietary fatty acids and eicosanoids. Activation of PPAR nuclear receptors results in the transcription of a number of insulin-responsive genes involved in the control of glucose and lipid metabolism. Among the overall effects of PPARy receptor activation are increased glucose metabolism and insulin sensitivity, and downregulation of insulin in liver and blood.2

Recent evidence suggests that thiazolidinediones actually preserve |3-cell function and protect cardiovascular and renal function in people with type 2 diabetes. Pioglitazone was also shown to reduce excess liver fat by over 50% in patients with nonalcoholic steatohepatitis, a fatty liver disease that can cause liver failure. This condition affects about 5% of Americans and occurs primarily as a result of obesity, insulin resistance, diabetes and elevated cholesterol. The progression of type 2 diabetes to more advanced stages may in many cases be halted by a combination of weight control, diet and antidiabetic medications such as pioglitazone.

X-Ray crystal structure of rosiglitazone bound to PPAR-y3

1. Treatm. Endocrinol. 2006, 5, 189-191; 2. Curr. Diabel. Rev 2007, 3, 67-74; 3. Nature 1998, 395, 137-143 (2PRG);

PART II. ANTIDIABETIC AGENTS

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