Abstract
The design and synthesis of a novel class of 2,3-dihydrobenzofuran-2-carboxylic acids as highly potent and subtype-selective PPARalpha agonists are reported. Systematic study of structure-activity relationships has identified several key structural elements within this class for maintaining the potency and subtype selectivity. Select compounds were evaluated in animal models of dyslipidemia using Syrian hamsters and male Beagle dogs, and all these compounds displayed excellent cholesterol- and triglyceride-lowering activity at dose levels that were much lower than the marketed weak PPARalpha agonist fenofibrate.
MeSH terms
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Animals
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Benzofurans / chemical synthesis*
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Benzofurans / chemistry
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Benzofurans / pharmacology
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Carboxylic Acids / chemical synthesis*
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Carboxylic Acids / chemistry
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Carboxylic Acids / pharmacology
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Cholesterol / blood
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Cricetinae
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Dogs
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Humans
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Hyperlipidemias / drug therapy
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Hypolipidemic Agents / chemical synthesis*
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Hypolipidemic Agents / chemistry
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Hypolipidemic Agents / pharmacology
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In Vitro Techniques
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Male
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Mesocricetus
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Molecular Conformation
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PPAR alpha / agonists*
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PPAR alpha / genetics
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Radioligand Assay
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Stereoisomerism
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Structure-Activity Relationship
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Transcriptional Activation
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Triglycerides / blood
Substances
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2-ethyl-5-(3-(2-chloro-4-(trifluoromethoxy)phenoxy)propoxy)-2,3-dihydro-1-benzofuran-2-carboxylic acid
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Benzofurans
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Carboxylic Acids
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Hypolipidemic Agents
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PPAR alpha
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Triglycerides
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Cholesterol