Novel selective small molecule agonists for peroxisome proliferator-activated receptor δ (PPARδ)—synthesis and biological activity

Sznaidman, Marcos L.; Haffner, Curt D.; Maloney, Patrick; Fivush, Adam M.; Chao, Esther Y.; Goreham, Donna M.; Sierra, Michael L.; LeGrumelec, Christelle; Xu, H. Eric; Montana, V.G.; Lambert, Millard H.; Willson, Timothy M.; Oliver, William R.; Sternbach, Daniel D.

doi:10.1016/s0960-894x(03)00207-5

Cited by 302 publications

(239 citation statements)

References 15 publications

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“…Consistent with a PPAR␤/␦-dependent mechanism, we demonstrated that induction of IL-1Ra secretion by rosiglitazone was abolished by transfection with a dominant-negative form of PPAR␤/␦. We showed further that a low concentration of GW-501516, a highly selective PPAR␤/␦ agonist (27,63,64), reproduced the stimulating effect of highdose rosiglitazone on IL-1Ra secretion. Taken together, these data demonstrate that rosiglitazone enhanced IL-1Ra secretion in a PPAR␤/␦-dependent manner and that this likely occurred because its relative affinity for PPAR isotypes was counterbalanced by the pattern of expression of PPAR isotypes in response to IL-1␤ stimulation.…”

Section: Discussionmentioning

confidence: 64%

Rosiglitazone induces interleukin‐1 receptor antagonist in interleukin‐1β–stimulated rat synovial fibroblasts via a peroxisome proliferator–activated receptor β/δ–dependent mechanism

Moulin¹,

Bianchi²,

Boyault³

et al. 2005

Arthritis & Rheumatism

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Objective. To study the potency of 2 peroxisome proliferator-activated receptor ␥ (PPAR␥) agonists, 15-deoxy-⌬ 12,14 -prostaglandin J 2 (15-deoxy-PGJ 2 ) and rosiglitazone, to modulate the expression of interleukin-1 receptor antagonist (IL-1Ra) in rat synovial fibroblasts.Methods. Levels of messenger RNA for IL-1Ra and PPAR isotypes (␣, ␤/␦, ␥) were assessed by realtime polymerase chain reaction in rat synovial fibroblasts exposed to 10 ng/ml of IL-1␤. PPAR levels were assessed by Western blotting and secreted IL-1Ra levels by immunoassay. The potency of PPAR␥ agonists and the PPAR␤/␦ agonist GW-501516 on IL-1Ra levels was tested in the range of 1-10 M and at 100 pM, respectively. The contribution of PPAR␥ to the effects of rosiglitazone on IL-1Ra secretion was examined either by its overexpression or by inhibition using wild-type or dominant-negative constructs and the antagonist GW-9662 (10 M), respectively. The dominant-negative strategy was also performed to investigate the possible contribution of PPAR␤/␦ and NF-B activation.Results. IL-1␤-induced IL-1Ra production was increased by 10 M rosiglitazone but was reduced dose-dependently by 15-deoxy-PGJ 2 . Both agonists lowered IL-1␤ secretion, but rosiglitazone alone reduced the imbalance of IL-1␤/IL-1Ra toward basal levels. Enhancement of IL-1␤-induced IL-1Ra production by rosiglitazone was not affected by PPAR␥ overexpression or by its inhibition with dominant-negative PPAR␥ or GW-9662. Inhibition of NF-B was also ineffective against rosiglitazone but abolished the stimulating effect of IL-1␤ on IL-1Ra. All PPAR isotypes were expressed constitutively in rat synoviocytes, but PPAR␥ decreased dramatically upon IL-1␤ exposure, whereas PPAR␤/␦ remained stable. Dominant-negative PPAR␤/␦ abolished the enhancement of IL-1Ra by rosiglitazone, whereas GW-501516 reproduced the effect of rosiglitazone on IL-1Ra secretion.Conclusion. Rosiglitazone stimulates IL-1Ra production by a PPAR␤/␦ mechanism in activated rat synovial fibroblasts, further contributing to its potential antiarthritic properties and opening new perspectives for the modulation of inflammatory genes by specific PPAR agonists in articular cells.

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Section: Discussionmentioning

confidence: 64%

Rosiglitazone induces interleukin‐1 receptor antagonist in interleukin‐1β–stimulated rat synovial fibroblasts via a peroxisome proliferator–activated receptor β/δ–dependent mechanism

Moulin¹,

Bianchi²,

Boyault³

et al. 2005

Arthritis & Rheumatism

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“…GW501516 was synthesized according to procedures previously described by others (Sznaidman et al 2003;Wei and Kozikowski 2003). It was characterized using 1 H-NMR (DMSO-d 6 ) and MS, and determined to be 99% pure based on HPLC analysis.…”

Section: Chemicalsmentioning

confidence: 99%

“…There are a number of possible explanations for the reported differences described for the effect of PPARβ/δ ligands on cell growth including differences between high affinity PPARβ/δ ligands (Berger et al 1999;Sznaidman et al 2003) and differences due to the presence or absence of serum. The present studies evaluated the possible influence of these variables using two different PPARβ/δ ligands (GW0742 and GW501516), and comparing the effects of these ligands in two human cancer cell lines in the presence or absence of serum.…”

Section: Introductionmentioning

confidence: 99%

Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) ligands inhibit growth of UACC903 and MCF7 human cancer cell lines

et al. 2008

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The development of peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) ligands for the treatment of diseases including metabolic syndrome, diabetes and obesity has been hampered due to contradictory findings on their potential safety. For example, while some reports show that ligand activation of PPARβ/δ promotes the induction of terminal differentiation and inhibition of cell growth, other reports suggest that PPARβ/δ ligands potentiate tumorigenesis by increasing cell proliferation. Some of the contradictory findings could be due in part to differences in the ligand examined, the presence or absence of serum in cell cultures, differences in cell lines, or differences in the method used to quantify cell growth. For these reasons, this study examined the effect of ligand activation of PPARβ/δ on cell growth of two human cancer cell lines, MCF7 (breast cancer) and UACC903 (melanoma) in the presence or absence of serum using two highly specific PPARβ/δ ligands, GW0742 or GW501516. Culturing cells in the presence of either GW0742 or GW501516 caused upregulation of the known PPARβ/δ target gene angiopoetin-like protein 4 (ANGPTL4). Inhibition of cell growth was observed in both cell lines cultured in the presence of either GW0742 or GW501516, and the presence or absence of serum had little influence on this inhibition. Results from the present studies demonstrate that ligand activation of PPARβ/δ inhibits the growth of both MCF7 and UACC903 cell lines and provide further evidence that PPARβ/δ ligands are not mitogenic in human cancer cell lines.

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“…Nevertheless, evidence from PPAR-δ knock-out mice and other experimental approaches revealed a broad spectrum of functions in embryo implantation, early development, wound healing and cancer development [6][7][8][9]. The important regulatory impact of PPAR-δ on whole-body fuel turnover was not recognised until potent and selective agonists became available [10][11][12][13]. The subsequent pharmacological studies promoted great interest in this receptor as a target for drug development [10,[13][14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Peroxisome proliferator-activated receptor-δ, a regulator of oxidative capacity, fuel switching and cholesterol transport

2006

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Synthetic agonists of peroxisome proliferatoractivated receptor (PPAR)-δ have shown a promising pharmacological profile in preclinical models of metabolic and cardiovascular disease. At present, the pharmaceutical development of these drugs exploits the potential to raise plasma HDL-cholesterol in animals and their insulinsensitising and glucose-lowering properties. PPAR-δ agonists have also proven to be powerful research tools that have provided insights into the role of fatty acid metabolism in human physiology and disease. Activation of PPAR-δ induces the expression of genes important for cellular fatty acid combustion and an associated increase in whole-body lipid dissipation. The predominant target tissue in this regard is skeletal muscle, in which PPAR-δ activation regulates the oxidative capacity of the mitochondrial apparatus, switches fuel preference from glucose to fatty acids, and reduces triacylglycerol storage. These changes counter the characteristic derangements of insulinresistant skeletal muscle but resemble the metabolic adaptation to regular physical exercise. Apart from effects on fuel turnover, there is evidence for direct antiatherogenic properties, because PPAR-δ activation increases cholesterol export and represses inflammatory gene expression in macrophages and atherosclerotic lesions. Whereas conclusions about the full potential of PPAR-δ as a drug target await the result of large scale clinical testing, ongoing investigation of this nuclear receptor has greatly improved our knowledge of the physiological regulation of wholebody fuel turnover and the interdependence of mitochondrial function and insulin sensitivity.

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Novel selective small molecule agonists for peroxisome proliferator-activated receptor δ (PPARδ)—synthesis and biological activity

Cited by 302 publications

References 15 publications

Rosiglitazone induces interleukin‐1 receptor antagonist in interleukin‐1β–stimulated rat synovial fibroblasts via a peroxisome proliferator–activated receptor β/δ–dependent mechanism

Rosiglitazone induces interleukin‐1 receptor antagonist in interleukin‐1β–stimulated rat synovial fibroblasts via a peroxisome proliferator–activated receptor β/δ–dependent mechanism

Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) ligands inhibit growth of UACC903 and MCF7 human cancer cell lines

Peroxisome proliferator-activated receptor-δ, a regulator of oxidative capacity, fuel switching and cholesterol transport

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