Design and synthesis of alpha-aryloxy-alpha-methylhydrocinnamic acids: a novel class of dual peroxisome proliferator-activated receptor alpha/gamma agonists.
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:
Animals, Binding, Competitive, Cell Line, Diabetes Mellitus, Type 2, Female, Humans, Hyperlipidemias, Hypoglycemic Agents, Hypolipidemic Agents, Phenylpropionates, Radioligand Assay, Rats, Rats, Zucker, Receptors, Cytoplasmic and Nuclear, Stereoisomerism, Structure-Activity Relationship, Thiophenes, Transcription Factors
Animals, Binding, Competitive, Cell Line, Diabetes Mellitus, Type 2, Female, Humans, Hyperlipidemias, Hypoglycemic Agents, Hypolipidemic Agents, Phenylpropionates, Radioligand Assay, Rats, Rats, Zucker, Receptors, Cytoplasmic and Nuclear, Stereoisomerism, Structure-Activity Relationship, Thiophenes, Transcription Factors
J Med Chem
Date: May. 06, 2004
PubMed ID: 15115385
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