Discovery of (2R)-2-(3-{3-[(4-Methoxyphenyl)carbonyl]-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl}phenoxy)butanoic Acid (MK-0533): A Novel Selective Peroxisome Proliferator-Activated Rec

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• 作者：John J. Acton ; III ; Taro E. Akiyama ; Ching H. Chang ; Lawrence Colwell ; Sheryl Debenham ; Thomas Doebber ; Monica Einstein ; Kun Liu ; Margaret E. McCann ; David E. Moller ; Eric S. Muise ; Yugen Tan ; John R.
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：July 9, 2009
• 年：2009
• 卷：52
• 期：13
• 页码：3846-3854
• 全文大小：241K
• 年卷期：v.52,no.13(July 9, 2009)
• ISSN：1520-4804

文摘

Peroxisome proliferator-activated receptor gamma (PPARγ) agonists are used to treat type 2 diabetes mellitus (T2DM). Widespread use of PPARγ agonists has been prevented due to adverse effects including weight gain, edema, and increased risk of congestive heart failure. Selective PPARγ modulators (SPPARγMs) have been identified that have antidiabetic efficacy and reduced toxicity in preclinical species. In comparison with PPARγ full agonists, SPPARγM 6 (MK0533) displayed diminished maximal activity (partial agonism) in cell-based transcription activation assays and attenuated gene signatures in adipose tissue. Compound 6 exhibited comparable efficacy to rosiglitazone and pioglitazone in vivo. However, with regard to the induction of untoward events, 6 displayed no cardiac hypertrophy, attenuated increases in brown adipose tissue, minimal increases in plasma volume, and no increases in extracellular fluid volume in vivo. Further investigation of 6 is warranted to determine if the improvement in mechanism-based side effects observed in preclinical species will be recapitulated in humans.