skin-targeted inhibition of ppar βδ by selective antagonists to treat ppar βδ – mediated psoriasis-like skin disease in vivoskin-targeted抑制pparβδ通过选择性拮抗剂治疗pparβδu2014u2014介导体内psoriasis-like皮肤病.pdfVIP

Skin-Targeted Inhibition of PPAR b/d by Selective Antagonists to Treat PPAR b/d – Mediated Psoriasis-Like Skin Disease In Vivo 1 1 1 5 5 5 4 Katrin Hack , Louise Reilly , Colin Palmer , Kevin D. Read , Suzanne Norval , Robert Kime , Kally Booth , John Foerster2,3* 1 Medical Research Institute, College of Medicine, Dentistry, and Nursing, University of Dundee, Dundee, Scotland, 2 Department of Dermatology, College of Medicine, Dentistry, and Nursing, University of Dundee, Dundee, Scotland, 3 Education Division, College of Medicine, Dentistry, and Nursing, University of Dundee, Dundee, Scotland, 4 Medical School Biological Resource Unit, College of Medicine, Dentistry, and Nursing, 5 Biological Chemistry and Drug Discovery Unit, College of Life Sciences, University of Dundee, Dundee, Scotland Abstract We have previously shown that peroxisome proliferator activating receptor ß/d (PPAR b/d is overexpressed in psoriasis. PPAR b/d is not present in adult epidermis of mice. Targeted expression of PPAR b/d 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 b/d activation contributes to psoriasis pathogenesis. Thus, inhibition of PPAR b/d might harbour therapeutical potential. Since PPAR b/d has pleiotropic functions in metabolism, skin- targeted inhibition offer the potential of reducing systemic adverse effects. Here, we report that three selective PPAR b/ d 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