title: Alpha-Lipoic acid-based PPARgamma agonists for treating inflammatory skin diseases.
abstract: Novel thiazolidinedione derivatives of the potent antioxidant, alpha-lipoic (thioctic, 1,2-dithiolane) acid, were prepared. The prototype N-(2-[4-[2,4-dioxo(1,3-thiazolidin-5-yl)methyl]phenoxy]ethyl)-5-(1,2-dithiolan-3-yl)- N-methylpentanamide (designated BP-1003), and dithioester derivatives thereof were shown to be potent activators of peroxisome proliferator-activated receptor gamma (PPARgamma) (EC(50) range 15-101 nM) and modest activators of PPARalpha (EC(50) 5 microM). Both the relatively hydrophobic dithiolane prototype, BP-1003, and its water-soluble dithioglycinate derivative, BP-1017, were shown to inhibit the proliferation of human keratinocytes and suppress the production of interleukin-2 by human peripheral lymphocytes to a greater extent than the antidiabetic thiazolidinedione, rosiglitazone. Both oral and topical administration of BP-1017 showed significant antiinflammatory effects in the oxazolone-sensitized mouse model of allergic contact dermatitis (ACD). These findings suggest that water-soluble lipoic acid-based thiazolidinediones may be efficacious as oral and topical agents for treating inflammatory skin conditions such as contact dermatitis, atopic dermatitis, and psoriasis.
authors.affiliation: Department Medicinal Chemistry, University of Mississippi, University, MS, USA.
authors.forename: Meenakshi S
authors.initials: MS
authors.lastname: Venkatraman
authors.forename: Amar
authors.initials: A
authors.lastname: Chittiboyina
authors.forename: Josef
authors.initials: J
authors.lastname: Meingassner
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Ho
authors.forename: James
authors.initials: J
authors.lastname: Varani
authors.forename: Charles N
authors.initials: CN
authors.lastname: Ellis
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Avery
authors.forename: Harrihar A
authors.initials: HA
authors.lastname: Pershadsingh
authors.forename: Theodore W
authors.initials: TW
authors.lastname: Kurtz
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Benson
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology*; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D017449:Dermatitis, Allergic Contact / Q000188:drug therapy*; D004195:Disease Models, Animal; D000882:Haplorhini; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects; D051379:Mice; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*; D008063:Thioctic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D007376:Interleukin-2; D047495:PPAR gamma; D013844:Thiazoles; D008063:Thioctic Acid