PPAR modulator

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

Contents

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. 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 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,[1] 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 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.

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.[2][3] 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.[4]

References

  1. ^ B. Brunmair et al. (2006). "Activation of PPAR-δ in isolated rat skeletal muscle switches fuel preference from glucose to fatty acids". Diabetologia 49 (11): 2713–22. doi:10.1007/s00125-006-0357-6. PMID 16960684. 
  2. ^ Fiévet C, Fruchart JC, Staels B (2006). "PPARalpha and PPARgamma dual agonists for the treatment of type 2 diabetes and the metabolic syndrome". Current opinion in pharmacology 6 (6): 606–14. doi:10.1016/j.coph.2006.06.009. PMID 16973418. 
  3. ^ Balakumar P, Rose M, Ganti SS, Krishan P, Singh M (2007). "PPAR dual agonists: are they opening Pandora's Box?". Pharmacol. Res. 56 (2): 91–8. doi:10.1016/j.phrs.2007.03.002. PMID 17428674. 
  4. ^ Staels B, Fruchart JC (2005). "Therapeutic roles of peroxisome proliferator-activated receptor agonists". Diabetes 54 (8): 2460–70. doi:10.2337/diabetes.54.8.2460. PMID 16046315. 
Insulin
Metformin# • Buformin‡ • Phenformin‡
TZDs (PPAR)
Meglitinides/"glinides"
Analogs/other insulins
fast-acting (Insulin lispro • Insulin aspart • Insulin glulisine) • short-acting (Regular insulin) • long-acting (Insulin glargine • Insulin detemir • NPH insulin) • ultra-long-acting (Insulin degludec†) • inhalable Exubera‡
Other
Amylin analog
SGLT2 inhibitors
Other

M: END

anat/phys/devp/horm

noco(d)/cong/tumr, sysi/epon

proc, drug (A10/H1/H2/H3/H5)
GI tract
Liver
Niacin and derivatives (HDL and LDL)
Blood vessels
Fibrates (PPAR)
Combinations
Other

M: MET

mt, k, c/g/r/p/y/i, f/h/s/l/o/e, a/u, n, m

k, cgrp/y/i, f/h/s/l/o/e, au, n, m, epon

m(A16/C10),i(k, c/g/r/p/y/i, f/h/s/o/e, a/u, n, m)