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Skin-targeted inhibition of PPAR β/δ by selective antagonists to treat PPAR β/δ-mediated psoriasis-like skin disease in vivo.

Hack K, Reilly L, Palmer C, Read KD, Norval S, Kime R, Booth K, Foerster J - PLoS ONE (2012)

Bottom Line: Since PPAR β/δ has pleiotropic functions in metabolism, skin-targeted inhibition offer the potential of reducing systemic adverse effects.These antagonists show efficacy in our transgenic mouse model in reducing psoriasis-like changes triggered by activation of PPAR β/δ.PPAR β/δ antagonists GSK0660 and compound 3 do not exhibit systemic drug accumulation after prolonged application to the skin, nor do they induce inflammatory or irritant changes.

View Article: PubMed Central - PubMed

Affiliation: Medical Research Institute, College of Medicine, Dentistry, and Nursing, University of Dundee, Dundee, Scotland.

ABSTRACT
We have previously shown that peroxisome proliferator activating receptor ß/δ (PPAR β/δ is overexpressed in psoriasis. PPAR β/δ is not present in adult epidermis of mice. Targeted expression of PPAR β/δ and activation by a selective synthetic agonist is sufficient to induce an inflammatory skin disease resembling psoriasis. Several signalling pathways dysregulated in psoriasis are replicated in this model, suggesting that PPAR β/δ activation contributes to psoriasis pathogenesis. Thus, inhibition of PPAR β/δ might harbour therapeutical potential. Since PPAR β/δ has pleiotropic functions in metabolism, skin-targeted inhibition offer the potential of reducing systemic adverse effects. Here, we report that three selective PPAR β/δ antagonists, GSK0660, compound 3 h, and GSK3787 can be formulated for topical application to the skin and that their skin concentration can be accurately quantified using ultra-high performance liquid chromatography (UPLC)/mass spectrometry. These antagonists show efficacy in our transgenic mouse model in reducing psoriasis-like changes triggered by activation of PPAR β/δ. PPAR β/δ antagonists GSK0660 and compound 3 do not exhibit systemic drug accumulation after prolonged application to the skin, nor do they induce inflammatory or irritant changes. Significantly, the irreversible PPAR β/δ antagonist (GSK3787) retains efficacy when applied topically only three times per week which could be of practical clinical usefulness. Our data suggest that topical inhibition of PPAR β/δ to treat psoriasis may warrant further exploration.

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PPAR β/δ selective antagonists used in this study.Chemical structures and in vitro pharmacodynamic data shown are taken from the references listed. The structure of the PPAR β/δ selective agonist GW501516 used in this study is given for comparison.
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pone-0037097-g001: PPAR β/δ selective antagonists used in this study.Chemical structures and in vitro pharmacodynamic data shown are taken from the references listed. The structure of the PPAR β/δ selective agonist GW501516 used in this study is given for comparison.

Mentions: PPAR β/δ isoform-selective antagonists have only recently been described [13]–[17]. For the present work we used the first one to be reported, GSK0660, based on high antagonist potential, high affinity, its documented anti-inflammatory effect [18], and a reported lack of bioavailability upon systemic administration [17], thus potentially increasing its usefulness as a skin specific targeting compound. In order to ensure that any effects seen in vivo are indeed due to PPAR β/δ antagonism and not caused by off-target effects related to the chemical structure of GSK0660, we also included an alternative antagonist, compound 3 h [13], in a subset of experiments. Compound 3 h was chosen because of its low reported Ki (11 nM), high competitive antagonist potency, as well as lack of activity on other PPAR isoforms [13], The structure and key properties of these antagonists are shown in figure 1. An alternative reported compound appears to be less isoform selective [14]. Finally, one additional PPAR β/δ antagonist irreversibly inactivates the receptor by forming a covalent bond (GSK3787) [15], [16]. This compound was included to address the feasibility of achieving treatment effects with less frequent dosing.


Skin-targeted inhibition of PPAR β/δ by selective antagonists to treat PPAR β/δ-mediated psoriasis-like skin disease in vivo.

Hack K, Reilly L, Palmer C, Read KD, Norval S, Kime R, Booth K, Foerster J - PLoS ONE (2012)

PPAR β/δ selective antagonists used in this study.Chemical structures and in vitro pharmacodynamic data shown are taken from the references listed. The structure of the PPAR β/δ selective agonist GW501516 used in this study is given for comparison.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3351437&req=5

pone-0037097-g001: PPAR β/δ selective antagonists used in this study.Chemical structures and in vitro pharmacodynamic data shown are taken from the references listed. The structure of the PPAR β/δ selective agonist GW501516 used in this study is given for comparison.
Mentions: PPAR β/δ isoform-selective antagonists have only recently been described [13]–[17]. For the present work we used the first one to be reported, GSK0660, based on high antagonist potential, high affinity, its documented anti-inflammatory effect [18], and a reported lack of bioavailability upon systemic administration [17], thus potentially increasing its usefulness as a skin specific targeting compound. In order to ensure that any effects seen in vivo are indeed due to PPAR β/δ antagonism and not caused by off-target effects related to the chemical structure of GSK0660, we also included an alternative antagonist, compound 3 h [13], in a subset of experiments. Compound 3 h was chosen because of its low reported Ki (11 nM), high competitive antagonist potency, as well as lack of activity on other PPAR isoforms [13], The structure and key properties of these antagonists are shown in figure 1. An alternative reported compound appears to be less isoform selective [14]. Finally, one additional PPAR β/δ antagonist irreversibly inactivates the receptor by forming a covalent bond (GSK3787) [15], [16]. This compound was included to address the feasibility of achieving treatment effects with less frequent dosing.

Bottom Line: Since PPAR β/δ has pleiotropic functions in metabolism, skin-targeted inhibition offer the potential of reducing systemic adverse effects.These antagonists show efficacy in our transgenic mouse model in reducing psoriasis-like changes triggered by activation of PPAR β/δ.PPAR β/δ antagonists GSK0660 and compound 3 do not exhibit systemic drug accumulation after prolonged application to the skin, nor do they induce inflammatory or irritant changes.

View Article: PubMed Central - PubMed

Affiliation: Medical Research Institute, College of Medicine, Dentistry, and Nursing, University of Dundee, Dundee, Scotland.

ABSTRACT
We have previously shown that peroxisome proliferator activating receptor ß/δ (PPAR β/δ is overexpressed in psoriasis. PPAR β/δ is not present in adult epidermis of mice. Targeted expression of PPAR β/δ and activation by a selective synthetic agonist is sufficient to induce an inflammatory skin disease resembling psoriasis. Several signalling pathways dysregulated in psoriasis are replicated in this model, suggesting that PPAR β/δ activation contributes to psoriasis pathogenesis. Thus, inhibition of PPAR β/δ might harbour therapeutical potential. Since PPAR β/δ has pleiotropic functions in metabolism, skin-targeted inhibition offer the potential of reducing systemic adverse effects. Here, we report that three selective PPAR β/δ antagonists, GSK0660, compound 3 h, and GSK3787 can be formulated for topical application to the skin and that their skin concentration can be accurately quantified using ultra-high performance liquid chromatography (UPLC)/mass spectrometry. These antagonists show efficacy in our transgenic mouse model in reducing psoriasis-like changes triggered by activation of PPAR β/δ. PPAR β/δ antagonists GSK0660 and compound 3 do not exhibit systemic drug accumulation after prolonged application to the skin, nor do they induce inflammatory or irritant changes. Significantly, the irreversible PPAR β/δ antagonist (GSK3787) retains efficacy when applied topically only three times per week which could be of practical clinical usefulness. Our data suggest that topical inhibition of PPAR β/δ to treat psoriasis may warrant further exploration.

Show MeSH
Related in: MedlinePlus