Abstract
A novel class of azetidinone acid-derived dual PPARalpha/gamma agonists has been synthesized for the treatment of diabetes and dyslipidemia. The preferred stereochemistry in this series for binding and functional agonist activity against both PPARalpha and PPARgamma receptors was shown to be 3S,4S. Synthesis, in vitro and in vivo activities of compounds in this series are described. A high-yielding method for N-arylation of azetidinone esters is also described.
MeSH terms
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Administration, Oral
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Animals
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Azetidines / chemical synthesis
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Azetidines / chemistry*
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Azetidines / pharmacology*
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Biological Availability
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Copper / pharmacology
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Crystallography, X-Ray
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Cytochrome P-450 Enzyme Inhibitors
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Diabetes Mellitus, Experimental / drug therapy
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Dyslipidemias / drug therapy
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels / metabolism
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Glucose / metabolism
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Mice
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Mice, Mutant Strains
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Molecular Structure
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PPAR alpha / agonists*
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PPAR alpha / metabolism
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PPAR gamma / agonists*
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PPAR gamma / metabolism
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Protein Conformation
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Stereoisomerism
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Structure-Activity Relationship
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Triglycerides / blood
Substances
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2-azetidinone
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Azetidines
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Cytochrome P-450 Enzyme Inhibitors
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels
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PPAR alpha
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PPAR gamma
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Triglycerides
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Copper
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Glucose