ABSTRACT
A series of novel derivatives of potent antioxidant vitamin, alpha-lipoic acid, and related analogues were designed, synthesized, and evaluated for their PPARgamma agonist activities. Compounds 9a and the water soluble analogue11e were found to be potent PPARgamma agonists. Compound 9a appeared to have a significant role in improving insulin sensitivity and reducing triglyceride levels in fa/fa rats as well as inhibited proliferation of a variety of normal and neoplastic cultured human cell types. These novel compounds may prove efficacious not only in the treatment of Type 2 diabetes, but also atherosclerosis, prevention of vascular restenosis, and inflammatory skin diseases.
Subject(s)
Hypolipidemic Agents/chemical synthesis , PPAR gamma/agonists , Phenylacetates/chemical synthesis , Thiazolidinediones/chemical synthesis , Thioctic Acid/analogs & derivatives , Thioctic Acid/chemical synthesis , Adipocytes/cytology , Adipocytes/drug effects , Adipogenesis/drug effects , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Differentiation/drug effects , Cell Proliferation/drug effects , Cells, Cultured , Crystallography, X-Ray , Drug Design , Humans , Hypolipidemic Agents/pharmacology , Insulin Resistance , Interleukins/biosynthesis , Keratinocytes/cytology , Keratinocytes/drug effects , Models, Molecular , Molecular Structure , PPAR gamma/chemistry , Phenylacetates/pharmacology , Rats , Rats, Zucker , Structure-Activity Relationship , Thiazolidinediones/pharmacology , Thioctic Acid/pharmacologyABSTRACT
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.