Abstract
Structural modifications around 8-HETE (8-hydroxyeicosatetraenoic acid), a natural agonist of the PPAR (peroxisome proliferator-activated receptor) nuclear receptors have led previously to the identification of a promising analog, the quinoline S 70655. Series of novel quinoline or benzoquinoline derivatives were designed through the modification of this lead. Variations of the nature of the aromatic core and of the side chains were carried out. The SAR studies indicated the high sensitivity of the upper acid chain to modifications as well as the strong effect of the length and size of the lipophilic side chain. They afforded several new promising PPARalpha/gamma dual agonists with a high PPARalpha activity in vitro.
MeSH terms
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Animals
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COS Cells
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Caprylates / chemical synthesis
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Caprylates / chemistry
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Caprylates / pharmacology
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Chlorocebus aethiops
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Diabetes Mellitus, Type 2 / drug therapy
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Drug Design
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Genes, Reporter
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Humans
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Hydroxyeicosatetraenoic Acids / chemistry*
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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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Kinetics
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Metabolic Syndrome / drug therapy
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PPAR alpha / genetics
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PPAR alpha / metabolism
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PPAR gamma / genetics
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PPAR gamma / metabolism
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Peroxisome Proliferator-Activated Receptors / genetics
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Peroxisome Proliferator-Activated Receptors / metabolism*
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Quinolines / chemical synthesis*
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Quinolines / chemistry
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Quinolines / pharmacology*
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Recombinant Fusion Proteins / agonists
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Recombinant Fusion Proteins / metabolism
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Structure-Activity Relationship
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Transcriptional Activation / drug effects
Substances
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Caprylates
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Hydroxyeicosatetraenoic Acids
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Hypoglycemic Agents
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PPAR alpha
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PPAR gamma
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Peroxisome Proliferator-Activated Receptors
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Quinolines
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Recombinant Fusion Proteins
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8-hydroxyeicosatetraenoic acid