PPARs
The peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor family of ligand-activated transcription factors that heterodimerize with retinoid X receptor (RXR) isoforms to regulate gene expression. Three subtypes of PPAR have been identified and cloned: α, δ (also known as β) and γ. Many endogenous ligands have been isolated for PPARs; these include prostacyclin, fatty acids, lysophosphatidic acid and leukotriene B4. PPARs play many important roles in the cell, including lipid homeostasis, cell proliferation, differentiation, adipogenesis and immune functions and are useful in the treatment of metabolic disease. The table below summarizes the pharmacological properties of these receptors.
PPAR Receptor Data
| Receptor Subtype | PPARα | PPARδ | PPARγ |
|---|---|---|---|
| Primary Distribution | Liver, adipose tissue, kidney, heart, skeletal muscle, large intestine | Ubiquitous | Adipose tissue, lymphoid tissue, colon, liver, heart |
| Tissue Function | Fatty acid synthesis and oxidation, gluconeogenesis, ketogenesis, lipoprotein assembly | Placental and gut development, fatty acid oxidation, adaptive thermogenesis, control of cell proliferation and differentiation, tissue repair | Adipocyte differentiation, glucose homeostasis |
| Human Disease Relevance | Atherosclerosis | Atherosclerosis | Obesity and insulin resistance, type II diabetes mellitus, hypertension, atherosclerosis, cancer |
| Featured Compounds | Ki Values (nM) | |||
|---|---|---|---|---|
| Agonists | Ciglitazone (1307) Clofibrate (0824) GW 0742 (2229) GW 7647 (1677) GW 1929 (1664) L-165,041 (1856) WY 14643 (1312) | > 1000* 50 1.1 0.006 > 10 10 5 | > 1000* > 100 0.001 6.2 > 10 0.53 60 | 3* ~ 500 2 1.1 0.0062 5.5 35 |
| Antagonists | GW 9662 (1508) | 0.032 | 2 | 0.0033 |
Potency values for PPAR ligands acting at human subtypes, unless otherwise stated. For full experimental details, please refer to the cited publications.
* Measured at murine receptors.
References
Nuclear Receptors Nomenclature Committee (1999) A unified nomenclature system for the nuclear receptor superfamily. Cell 97 161. Willson et al (1996) The structure-activity relationship between peroxisome proliferator receptor γ agonism and the antihyperglycemic activity of thiazolidinediones. J.Med.Chem. 39 665. Willson et al (2000) The PPARs: from orphan receptors to drug discovery. J.Med.Chem. 43 527. Brown et al (2001) Identifi cation of a subtype selective human PPARα agonist through parallel-array synthesis. Bioorg.Med.Chem.Lett. 11 1225. Wright et al (2000) A synthetic antagonist for the peroxisome proliferator-activated receptor γ inhibits adipocyte differentiation. J.Biol.Chem. 275 1873. Leesnitzer et al (2002) Functional consequences of cysteine modifi cation in the ligand binding sites of peroxisome proliferator activated receptors by GW9662. Biochemistry 41 6640. Sznaidman et al (2003) Novel selective small molecule agonist for peroxisome proliferator-activated receptor γ (PPARγ) - Synthesis and biological activity. Bioorg.Med.Chem.Lett. 13 1517.