Alpha-Lipoic acid-based PPARgamma agonists for treating inflammatory skin diseases.
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.
Venkatraman
Meenakshi S
MS
Department Medicinal Chemistry, University of Mississippi, University, MS, USA.
Chittiboyina
Amar
A
Meingassner
Josef
J
Ho
Christopher I
CI
Varani
James
J
Ellis
Charles N
CN
Avery
Mitchell A
MA
Pershadsingh
Harrihar A
HA
Kurtz
Theodore W
TW
Benson
Stephen C
SC
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*
D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D007376:Interleukin-2; D047495:PPAR gamma; D013844:Thiazoles; D008063:Thioctic Acid