title: Skin-targeted inhibition of PPAR β/δ by selective antagonists to treat PPAR β/δ-mediated psoriasis-like skin disease in vivo.
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.
authors.affiliation: Medical Research Institute, College of Medicine, Dentistry, and Nursing, University of Dundee, Dundee, Scotland.
authors.forename: Katrin
authors.initials: K
authors.lastname: Hack
authors.forename: Louise
authors.initials: L
authors.lastname: Reilly
authors.forename: Colin
authors.initials: C
authors.lastname: Palmer
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Read
authors.forename: Suzanne
authors.initials: S
authors.lastname: Norval
authors.forename: Robert
authors.initials: R
authors.lastname: Kime
authors.forename: Kally
authors.initials: K
authors.lastname: Booth
authors.forename: John
authors.initials: J
authors.lastname: Foerster
mesh_terms: D000287:Administration, Topical; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009824:Ointments; D047495:PPAR gamma / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D048068:PPAR-beta / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011565:Psoriasis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012869:Skin Absorption; D013450:Sulfones / Q000008:administration & dosage / Q000493:pharmacokinetics; D013876:Thiophenes / Q000008:administration & dosage / Q000493:pharmacokinetics
chemical_list: C547957:4-chloro-N-(2-((5-trifluoromethyl-2-pyridyl)sulfonyl)ethyl)benzamide; D001549:Benzamides; C529769:GSK0660; D009824:Ointments; D047495:PPAR gamma; D048068:PPAR-beta; D011994:Recombinant Proteins; D013450:Sulfones; D013876:Thiophenes