PPAR modulator

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

Classification

PPARα and PPARγ are the molecular targets of a number of marketed drugs. The three main classes of PPAR drugs are:

PPAR-alpha modulators

PPAR-alpha is the main target of fibrate drugs, a class of amphipathic carboxylic acids (clofibrate, gemfibrozil, ciprofibrate, bezafibrate, and fenofibrate). They were originally indicated for cholesterol disorders (generally as an adjunctive to statins) and more recently for disorders that feature high triglycerides.

PPAR-delta modulators

PPAR-delta 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.cite journal | author = B. Brunmair et al. | title = Activation of PPAR-δ in isolated rat skeletal muscle switches fuel preference from glucose to fatty acids | journal = Diabetologia | volume = 49 | issue = 11 | pages = 2713–22 | year = 2006 | doi = 10.1007/s00125-006-0357-6 | issn = 0012-186X (Print) 1432-0428 (Online)]

PPAR-gamma modulators

PPAR-gamma is the main target of the drug class of thiazolidinediones (TZDs), used in diabetes mellitus and other diseases that feature insulin resistance. It is also mildly activated by certain NSAIDs (such as ibuprofen) and indoles. Known inhibitors include the experimental agent GW-9662.

They are also used in treating hyperlipidaemia in atherosclerosis. Here they act by increasing the expression of ABCA1, which transports extra-hepatic cholesterol into HDL. Increased uptake and excretion from the liver therefore follows.

Dual-PPAR modulators

A fourth class of "dual", "balanced" or "pan" PPAR ligands, 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.cite journal | author = Fiévet C, Fruchart JC, Staels B | title = PPARalpha and PPARgamma dual agonists for the treatment of type 2 diabetes and the metabolic syndrome | journal = Current opinion in pharmacology | volume = 6 | issue = 6 | pages = 606–14 | year = 2006 | pmid = 16973418 | doi = 10.1016/j.coph.2006.06.009 | issn = ] cite journal | author = Balakumar P, Rose M, Ganti SS, Krishan P, Singh M | title = PPAR dual agonists: are they opening Pandora's Box? | journal = Pharmacol. Res. | volume = 56 | issue = 2 | pages = 91–8 | year = 2007 | pmid = 17428674 | doi = 10.1016/j.phrs.2007.03.002 | issn = ] These include the experimental compounds aleglitazar, muraglitazar and tesaglitazar. In addition, there is continuing research and development of new PPAR modulators for additional therapeutic indications.cite journal | author = Staels B, Fruchart JC | title = Therapeutic roles of peroxisome proliferator-activated receptor agonists | journal = Diabetes | volume = 54 | issue = 8 | pages = 2460–70 | year = 2005 | pmid = 16046315 | doi = 10.2337/diabetes.54.8.2460 | issn = ]

References