Abstract
A series of 2-aryloxy-2-methyl-propionic acid compounds and related analogues were designed, synthesized, and evaluated for their PPAR agonist activities. 2-[(5,7-Dipropyl-3-trifluoromethyl)-benzisoxazol-6-yloxy]-2-methylpropionic acid (4) was identified as a PPARalpha/gamma dual agonist with relative PPARalpha selectivity and demonstrated potent efficacy in lowering both glucose and lipids in animal models without causing body weight gain. The PPARalpha activity of 4 appeared to have played a significant role in lowering glucose levels in db/db mice.
MeSH terms
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3T3-L1 Cells
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Animals
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Blood Glucose / drug effects
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COS Cells
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Carrier Proteins / biosynthesis
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Carrier Proteins / genetics
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Chlorocebus aethiops
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Cholesterol / blood
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Diabetes Mellitus, Type 2 / drug therapy*
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Dogs
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Fatty Acid-Binding Proteins
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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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Isoxazoles / chemical synthesis*
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Isoxazoles / chemistry
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Isoxazoles / pharmacology
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Mice
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Mice, Obese
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PPAR alpha / agonists*
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PPAR gamma / agonists*
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Propionates / chemical synthesis*
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Propionates / chemistry
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Propionates / pharmacology
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RNA, Messenger / biosynthesis
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Radioligand Assay
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Structure-Activity Relationship
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Transcriptional Activation
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Triglycerides / blood
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Weight Gain
Substances
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2-((5,7-dipropyl-3-trifluoromethyl)benzisoxazol-6-yloxy)-2-methylpropionic acid
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Blood Glucose
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Carrier Proteins
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Fatty Acid-Binding Proteins
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Hypoglycemic Agents
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Hypolipidemic Agents
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Isoxazoles
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PPAR alpha
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PPAR gamma
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Propionates
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RNA, Messenger
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Triglycerides
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Cholesterol