Abstract
The design and synthesis of the dual peroxisome proliferator activated receptor (PPAR) alpha/gamma agonist (S)-2-methyl-3-[4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)ethoxy]phenyl]-2-phenoxypropionic acid (2) for the treatment of type 2 diabetes and associated dyslipidemia are described. 2 possesses a potent dual hPPAR alpha/gamma agonist profile (IC(50) = 28 and 10 nM; EC(50) = 9 and 4 nM, respectively, for hPPARalpha and hPPARgamma). In preclinical models, 2 substantially improves insulin sensitivity and potently reverses diabetic hyperglycemia while significantly improving overall lipid homeostasis.
MeSH terms
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Animals
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Binding, Competitive
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Cell Line
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Diabetes Mellitus, Type 2 / drug therapy
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Female
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Humans
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Hyperlipidemias / drug therapy
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Hypoglycemic Agents / chemical synthesis*
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Hypoglycemic Agents / chemistry
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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 / pharmacology
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Phenylpropionates / chemical synthesis*
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Phenylpropionates / chemistry
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Phenylpropionates / pharmacology
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Radioligand Assay
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Rats
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Rats, Zucker
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Receptors, Cytoplasmic and Nuclear / agonists*
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Stereoisomerism
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Structure-Activity Relationship
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Thiophenes / chemical synthesis*
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Thiophenes / chemistry
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Thiophenes / pharmacology
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Transcription Factors / agonists*
Substances
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2-methyl-3-(4-(2-(5-methyl-2-thiophen-2-yloxazol-4-yl)ethoxy)phenyl)-2-phenoxypropionic acid
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Hypoglycemic Agents
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Hypolipidemic Agents
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Phenylpropionates
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Receptors, Cytoplasmic and Nuclear
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Thiophenes
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Transcription Factors