Abstract
A series of chromane-2-carboxylic acid derivatives was synthesized and evaluated for PPAR agonist activities. A structure-activity relationship was developed toward PPARalpha/gamma dual agonism. As a result, (2R)-7-(3-[2-chloro-4-(4-fluorophenoxy)phenoxy]propoxy)-2-ethylchromane-2-carboxylic acid (48) was identified as a potent, structurally novel, selective PPARalpha/gamma dual agonist. Compound 48 exhibited substantial antihyperglycemic and hypolipidemic activities when orally administered in three different animal models: the db/db mouse type 2 diabetes model, a Syrian hamster lipid model, and a dog lipid model.
MeSH terms
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Animals
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Benzopyrans / chemical synthesis*
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Benzopyrans / chemistry
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Benzopyrans / pharmacokinetics
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Benzopyrans / pharmacology
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Chromans / chemical synthesis*
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Chromans / chemistry
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Chromans / pharmacokinetics
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Chromans / pharmacology
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Cricetinae
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Diabetes Mellitus, Type 2 / drug therapy
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Diabetes Mellitus, Type 2 / genetics
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Dogs
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Humans
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Hypoglycemic Agents / chemical synthesis*
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Hypoglycemic Agents / chemistry
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Hypoglycemic Agents / pharmacokinetics
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Hypoglycemic Agents / pharmacology
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Hypolipidemic Agents / chemical synthesis*
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Hypolipidemic Agents / chemistry
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Hypolipidemic Agents / pharmacokinetics
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Hypolipidemic Agents / pharmacology
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Macaca mulatta
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Male
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Mesocricetus
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Mice
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Phenyl Ethers / chemical synthesis*
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Phenyl Ethers / chemistry
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Phenyl Ethers / pharmacokinetics
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Phenyl Ethers / pharmacology
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Rats
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Rats, Sprague-Dawley
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Receptors, Cytoplasmic and Nuclear / agonists*
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Receptors, Cytoplasmic and Nuclear / genetics
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Receptors, Cytoplasmic and Nuclear / metabolism
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Stereoisomerism
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Structure-Activity Relationship
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Trans-Activators / chemical synthesis
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Trans-Activators / chemistry
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Trans-Activators / pharmacology
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Transcription Factors / agonists*
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Transcription Factors / genetics
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Transcription Factors / metabolism
Substances
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7-(3-(2-chloro-4-(4-fluorophenoxy)phenoxy)propoxy)-2-ethylchromane-2-carboxylic acid
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Benzopyrans
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Chromans
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Hypoglycemic Agents
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Hypolipidemic Agents
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Phenyl Ethers
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Receptors, Cytoplasmic and Nuclear
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Trans-Activators
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Transcription Factors