Abstract
A series of ureidofibrate-like derivatives was prepared and assayed for their PPAR functional activity. A calorimetric approach was used to characterize PPARγ-ligand interactions, and docking experiments and X-ray studies were performed to explain the observed potency and efficacy. R-1 and S-1 were selected to evaluate several aspects of their biological activity. In an adipogenic assay, both enantiomers increased the expression of PPARγ target genes and promoted the differentiation of 3T3-L1 fibroblasts to adipocytes. In vivo administration of these compounds to insulin resistant C57Bl/6J mice fed a high fat diet reduced visceral fat content and body weight. Examination of different metabolic parameters showed that R-1 and S-1 are insulin sensitizers. Notably, they also enhanced the expression of hepatic PPARα target genes indicating that their in vivo effects stemmed from an activation of both PPARα and γ. Finally, the capability of R-1 and S-1 to inhibit cellular proliferation in colon cancer cell lines was also evaluated.
Publication types
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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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Adipocytes / metabolism
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Benzoxazoles / chemical synthesis
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Benzoxazoles / chemistry*
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Benzoxazoles / pharmacology
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Body Weight / drug effects
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Calorimetry
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Cell Differentiation / drug effects
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Cell Line
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Crystallography, X-Ray
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Drug Partial Agonism
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Drug Screening Assays, Antitumor
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Fibric Acids / chemistry*
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Fibroblasts / cytology
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Fibroblasts / drug effects
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Fibroblasts / metabolism
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Gene Expression Profiling
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Humans
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Insulin Resistance
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Intra-Abdominal Fat / drug effects
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Liver / drug effects
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Liver / metabolism
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Mice
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Mice, Inbred C57BL
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Models, Molecular
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PPAR alpha / agonists
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PPAR alpha / genetics
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PPAR alpha / metabolism*
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PPAR gamma / agonists
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PPAR gamma / genetics
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PPAR gamma / metabolism*
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Propionates / chemical synthesis
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Propionates / chemistry*
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Propionates / pharmacology
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Stereoisomerism
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Structure-Activity Relationship
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Urea / chemistry*
Substances
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Antineoplastic Agents
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Benzoxazoles
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Fibric Acids
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PPAR alpha
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PPAR gamma
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Propionates
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Urea