PPAR modulators are drugs which act upon the peroxisome proliferator-activated receptor

Peroxisome proliferator-activated receptor

In the field of molecular biology, the peroxisome proliferator-activated receptors are a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes...

.

Classification

PPARα and PPARγ are the molecular targets of a number of marketed drug

Drug

A drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...

s. The three main classes of PPAR drugs are:

PPAR-alpha modulators

PPAR-alpha

Peroxisome proliferator-activated receptor alpha

Peroxisome proliferator-activated receptor alpha , also known as NR1C1 , is a nuclear receptor protein that in humans is encoded by the PPARA gene.- Function :...

 is the main target of fibrate

Fibrate

In pharmacology, the fibrates are a class of amphipathic carboxylic acids. They are used for a range of metabolic disorders, mainly hypercholesterolemia , and are therefore hypolipidemic agents.- Members :...

 drugs

Medication

A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...

, a class of amphipathic carboxylic acids (clofibrate

Clofibrate

Clofibrate is a fibrate. It is a lipid lowering agent used for controlling the high cholesterol and triacylglyceride level in the blood. It increases lipoprotein lipase activity to promote the conversion of VLDL to LDL, and hence reduce the level of VLDL...

, gemfibrozil

Gemfibrozil

Gemfibrozil is the generic name for an oral drug used to lower lipid levels. It belongs to a group of drugs known as fibrates. It is most commonly sold as the brand name, Lopid...

, ciprofibrate

Ciprofibrate

Ciprofibrate is a fibrate.Crystalline powder white or almost white.Melting point about 115 to 120°C....

, bezafibrate

Bezafibrate

Bezafibrate is a fibrate drug used for the treatment of hyperlipidaemia. It helps to lower LDL cholesterol and triglyceride in the blood, and increase HDL.-Mode of action:...

, and fenofibrate

Fenofibrate

Fenofibrate is a drug of the fibrate class. Fenofibrate was developed by Groupe Fournier SA, before it was acquired in 2005 by Solvay Pharmaceutical, a business unit owned by the Belgian corporation, Solvay S.A. In 2009 Solvay Pharmaceutical was acquired by Abbott Laboratories. It is mainly used to...

). They were originally indicated for cholesterol

Cholesterol

Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...

 disorders (generally as an adjunctive to statin

Statin

Statins are a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver. Increased cholesterol levels have been associated with cardiovascular diseases, and statins are therefore used in the...

s) and more recently for disorders that feature high triglyceride

Triglyceride

A triglyceride is an ester derived from glycerol and three fatty acids. There are many triglycerides, depending on the oil source, some are highly unsaturated, some less so....

s. Many of them increase the risk of cancer to the point where they eliminate the survival benefit of reduced heart disease.

PPAR-delta modulators

PPAR-delta

Peroxisome proliferator-activated receptor delta

Peroxisome proliferator-activated receptor beta or delta , also known as NR1C2 is a nuclear receptor that in humans is encoded by the PPARD gene....

 is the main target of a research chemical named GW501516. It has been shown that agonism of PPAR-delta changes the body's fuel preference from glucose to lipids, but ironically improves metabolic syndrome (which is characterized by the body being unable to efficiently deal with glucose resulting in insulin resistance and sometimes diabetes).

PPAR-gamma modulators

PPAR-gamma

Peroxisome proliferator-activated receptor gamma

Peroxisome proliferator-activated receptor gamma , also known as the glitazone receptor, or NR1C3 is a type II nuclear receptor that in humans is encoded by the PPARG gene.Two isoforms of PPARG are detected in the human and in the mouse: PPAR-γ1 and...

 is the main target of the drug class of thiazolidinedione

Thiazolidinedione

The thiazolidinediones , also known as glitazones, are a class of medications used in the treatment of diabetes mellitus type 2. They were introduced in the late 1990s.- Mechanism of action :...

s (TZDs), used in diabetes mellitus

Diabetes mellitus

Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...

 and other diseases that feature insulin resistance

Insulin resistance

Insulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...

. It is also mildly activated by certain NSAIDs (such as ibuprofen

Ibuprofen

Ibuprofen is a nonsteroidal anti-inflammatory drug used for relief of symptoms of arthritis, fever, as an analgesic , especially where there is an inflammatory component, and dysmenorrhea....

) and indole

Indole

Indole is an aromatic heterocyclic organic compound. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered nitrogen-containing pyrrole ring. Indole is a popular component of fragrances and the precursor to many pharmaceuticals. Compounds that contain an...

s. Known inhibitors include the experimental agent GW-9662.

They are also used in treating hyperlipidaemia in atherosclerosis

Atherosclerosis

Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...

. Here they act by increasing the expression of ABCA1

ABCA1

ATP-binding cassette transporter ABCA1 , also known as the cholesterol efflux regulatory protein is a protein which in humans is encoded by the ABCA1 gene...

, which transports extra-hepatic cholesterol into HDL. Increased uptake and excretion from the liver therefore follows.

They may cause fluid retention and heart failure in those with weak hearts.

Dual-PPAR modulators

A fourth class of "dual", "balanced" or "pan" PPAR ligands, so-called glitazars, which bind two or more PPAR isoforms, are currently under active investigation for treatment of a larger subset of the symptoms of the metabolic syndrome

Metabolic syndrome

Metabolic syndrome is a combination of medical disorders that, when occurring together, increase the risk of developing cardiovascular disease and diabetes. It affects one in five people in the United States and prevalence increases with age...

. These include the experimental compounds aleglitazar

Aleglitazar

Aleglitazar is a peroxisome proliferator-activated receptor agonist with affinity to PPARα and PPARγ, which is being developed by Hoffmann–La Roche for the treatment of type II diabetes. It is currently in phase II clinical trials....

, muraglitazar

Muraglitazar

Muraglitazar is a peroxisome proliferator-activated receptor agonist with affinity to PPARα and PPARγ.The drug had completed phase III clinical trials, however in May, 2006 Bristol-Myers Squibb announced that it had discontinued further development.Data on muraglitazar is relatively less due to...

 and tesaglitazar

Tesaglitazar

Tesaglitazar is a peroxisome proliferator-activated receptor agonist with affinity to PPARα and PPARγ, proposed for type 2 diabetes.The drug had completed several phase III clinical trials, however in May, 2006 AstraZeneca announced that it had discontinued further development....

. In addition, there is continuing research and development of new PPAR modulators for additional therapeutic indications.