Abstract
Utilizing medicinal chemistry design strategies such as benzo splitting and ring expansion, we converted PPARalpha/gamma dual agonist 1 to selective PPARgamma agonists 19 and 20. Compounds 19 and 20 were 2- to 4-fold better than rosiglitazone at PPARgamma receptor, with 80- to 100-fold PPARgamma selectivity over PPARalpha receptor. X-ray cocrystal studies in PPARgamma and modeling studies in PPARalpha give molecular insights for the improved PPARgamma potency and selectivity for 19 when compared to 1.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Crystallography, X-Ray
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Hydroxybutyrates / chemical synthesis*
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Hydroxybutyrates / chemistry
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Hypoglycemic Agents / chemical synthesis*
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Hypoglycemic Agents / chemistry
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Models, Molecular
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PPAR alpha / agonists
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PPAR gamma / agonists*
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Protein Isoforms / agonists
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Quinolines / chemical synthesis*
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Quinolines / chemistry
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Rosiglitazone
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Structure-Activity Relationship
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Thiazolidinediones / chemistry
Substances
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2-(1-(3-(4-(biphenyl-4-carbonyl)-2-propylphenoxy)propyl)-1,2,3,4-tetrahydroquinolin-5-yloxy)-2-methylpropionic acid
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Hydroxybutyrates
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Hypoglycemic Agents
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PPAR alpha
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PPAR gamma
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Protein Isoforms
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Quinolines
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Thiazolidinediones
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Rosiglitazone