Design and Synthesis of α-Aryloxy-α-methylhydrocinnamic Acids:  A Novel Class of Dual Peroxisome Proliferator-Activated Receptor α/γ Agonists

• Published in: Journal of medicinal chemistry Vol. 47; no. 10; pp. 2422 - 2425
• Main Authors: Xu, Yanping, Rito, Christopher J, Etgen, Garret J, Ardecky, Robert J, Bean, James S, Bensch, William R, Bosley, Jacob R, Broderick, Carol L, Brooks, Dawn A, Dominianni, Samuel J, Hahn, Patric J, Liu, Sha, Mais, Dale E, Montrose-Rafizadeh, Chahrzad, Ogilvie, Kathy M, Oldham, Brian A, Peters, Mary, Rungta, Deepa K, Shuker, Anthony J, Stephenson, Gregory A, Tripp, Allie E, Wilson, Sarah B, Winneroski, Leonard L, Zink, Richard, Kauffman, Raymond F, McCarthy, James R
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 06-05-2004
• Subjects: Animals; Binding, Competitive; Biological and medical sciences; Cell Line; Diabetes Mellitus, Type 2 - drug therapy; Female; General and cellular metabolism. Vitamins; Humans; Hyperlipidemias - drug therapy; Hypoglycemic Agents - chemical synthesis; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacology; Hypolipidemic Agents - chemical synthesis; Hypolipidemic Agents - chemistry; Hypolipidemic Agents - pharmacology; Medical sciences; Pharmacology. Drug treatments; Phenylpropionates - chemical synthesis; Phenylpropionates - chemistry; Phenylpropionates - pharmacology; Radioligand Assay; Rats; Rats, Zucker; Receptors, Cytoplasmic and Nuclear - agonists; Stereoisomerism; Structure-Activity Relationship; Thiophenes - chemical synthesis; Thiophenes - chemistry; Thiophenes - pharmacology; Transcription Factors - agonists; Agonist; Ether; Rat; Rodentia; PPAR-γ receptor; Triglyceride; In vitro; In vivo; PPAR-α receptor; Thiophene derivatives; Vertebrata; Hypoglycemic agent; Sulfur heterocycle; Mammalia; Structure activity relation; Carboxylic acid; Cholesterol HDL; Animal; Chemical synthesis; Oxazole derivatives; Antilipemic agent; Oxygen nitrogen heterocycle
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0342616

The design and synthesis of the dual peroxisome proliferator activated receptor (PPAR) α/γ 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 α/γ agonist profile (IC50 = 28 and 10 nM; EC50 = 9 and 4 nM, respectively, for hPPARα and hPPARγ). In preclinical models, 2 substantially improves insulin sensitivity and potently reverses diabetic hyperglycemia while significantly improving overall lipid homeostasis.