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What is Rosiglitazone?

            Rosiglitazone Maleate is a hyperglycemic agent that works to lower the resistance to insulin in fat, liver and muscle cells and also by stopping abnormalities and dysfunctions in beta-cells. It is in the class of drugs called thiazolidenediones. Another member of this class of drugs, troglitazone, that was introduced in 1997, but had to be withdrawn from use due to cases of toxicity in the liver. Rosiglitazone shows no signs of causing this same toxicity and is therefore safe to use. By targeting this resistance at the cellular level, Rosiglitazone attaches itself to specific protein receptors called the peroxisome proliferator activated receptor (PPAR)g receptor, which in turn attach themselves to specific base sequences in DNA which causes amongst other things, proteins to be produced that help lower the production of glucose, or raise the sensitivity to insulin, this depends on where the proteins are situated. The cell will then take more glucose in, and therefore lower the amount of sugar in the bloodstream. There are two types of Rosiglitazone, and they are structurally similar in that they look like a left hand and a right hand. Rosiglitazone, being a synthetic compound is not found anywhere out of the laboratory. Therefore its natural abundance is 0 percent. It is obtained through a number of complex chemical synthesis'. There is also no natural density of Rosiglitazone. This is because it depends on the way it is created. As it is a chemical synthesis, there are many different states in which it can be prepared ranging from crystalline to powder states, all of which will vary in density. Rosiglitazone was first discovered by Dr Richard M. Hindley in the laboratories of the pharmaceutical company,  Beechem Group plc. The patent was granted on 26 March 1991 (USPTO No. 5,002,953). The actual date of discovery is not available in the public domain. The New Drug Application to the Food and Drug Administration for the use of rosiglitazone for the treatment of type 2 diabetes was approved on 25 May 1999.

 

This is important to understand, because when an agent like Rosiglitazone, tries to attach itself to a receptor like the PPARg receptor, it has to fit very well, or it will not have any effect. The image above shows that only the S- type of Rosiglitazone will fit well into the pocket of the PPARg receptor.

 

Rosiglitazone is mainly used for patients with the type 2 variety of diabetes. In addition to decreasing blood/sugar levels in patients, Rosiglitazone has also been shown to lower triglyceride and insulin levels. It also has been accredited to stop a certain disease in the kidney, cell nephropathy. Rosiglitazone is also called Avandia, that varies in dosage, and is produced by GlaxoSmithKline.

 

 

Above is a picture of two agents that are bound to the PPARg receptor. Rosiglitazone is the green structure and molecule GI 262570

is the teal structure. Notice how the teal structure is larger, and it seems to be better wrapped around coil. This is very important, because the better fitting the agent is, the more potent and better working the agent will be.

           

 

Adapted from Willson et al (2000), Gampe et al  (2000), Henke et al (1998), Henke et al  (2000)

 

The image above shows how potent a few of the ‘glitazone’ drugs are. The log graph above shows how potent the agent is with a smaller value meaning more potent. This graph clearly shows how the agent GI262570 is quite a lot more potent than Rosiglitazone. This is because the agent GI262570 fits around the PPaRy receptor a lot better than Rosiglitazone does.

 How to use the 3-d Model:

To rotate the model simply click on the box with the left mouse button and drag the mouse. For more options such as different types of models click on the box with the right mouse button and you will get a number of choices displayed in a menu

 

 

Here are some of the physical statistics about the Avandia drug and Rosiglitazone.

 

 

 

Pictures on this page taken from a GlaxoSmithKline presentation