Design and synthesis of the first generation of dithiolane thiazolidinedione- and phenylacetic acid-based PPARgamma agonists

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 h...

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Bibliographic Details
Published inJournal of medicinal chemistry Vol. 49; no. 14; pp. 4072 - 4084
Main Authors Chittiboyina, Amar G, Venkatraman, Meenakshi S, Mizuno, Cassia S, Desai, Prashant V, Patny, Akshay, Benson, Stephen C, Ho, Christopher I, Kurtz, Theodore W, Pershadsingh, Harrihar A, Avery, Mitchell A
Format Journal Article
LanguageEnglish
Published United States 13.07.2006
Subjects
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 - chemical synthesis
Hypolipidemic Agents - pharmacology
Insulin Resistance
Interleukins - biosynthesis
Keratinocytes - cytology
Keratinocytes - drug effects
Models, Molecular
Molecular Structure
Phenylacetates - chemical synthesis
Phenylacetates - pharmacology
PPAR gamma - agonists
PPAR gamma - chemistry
Rats
Rats, Zucker
Structure-Activity Relationship
Thiazolidinediones - chemical synthesis
Thiazolidinediones - pharmacology
Thioctic Acid - analogs & derivatives
Thioctic Acid - chemical synthesis
Thioctic Acid - pharmacology
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Summary: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.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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ISSN:0022-2623