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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adipocytes / cytology
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Adipocytes / drug effects
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Adipogenesis / drug effects
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
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Anti-Inflammatory Agents, Non-Steroidal / chemistry
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / pharmacology
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Cell Differentiation / drug effects
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Cell Proliferation / drug effects
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Cells, Cultured
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Crystallography, X-Ray
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Drug Design
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Humans
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Hypolipidemic Agents / chemical synthesis*
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Hypolipidemic Agents / pharmacology
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Insulin Resistance
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Interleukins / biosynthesis
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Keratinocytes / cytology
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Keratinocytes / drug effects
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Models, Molecular
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Molecular Structure
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PPAR gamma / agonists*
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PPAR gamma / chemistry
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Phenylacetates / chemical synthesis*
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Phenylacetates / pharmacology
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Rats
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Rats, Zucker
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Structure-Activity Relationship
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Thiazolidinediones / chemical synthesis*
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Thiazolidinediones / pharmacology
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Thioctic Acid / analogs & derivatives*
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Thioctic Acid / chemical synthesis*
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Thioctic Acid / pharmacology
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Antineoplastic Agents
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Hypolipidemic Agents
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Interleukins
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N-(2-(4-((2,4-dioxo-1,3-thiazolidin-5-yl)methyl)phenoxy)ethyl)-5-(1,2-dithiolan-3-yl)-N-methylpentanamide
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PPAR gamma
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Phenylacetates
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Thiazolidinediones
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Thioctic Acid