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 Receptor γ Modulator for the Treatment of Type 2 Diabetes Mellitus with a Reduced Potential to Increase Plasma and Extracellular Fluid Volume

被引：45

作者：

Acton, John J., III ^{[1
]}

Akiyama, Taro E. ^{[1
]}

Chang, Ching H. ^{[1
]}

Colwell, Lawrence ^{[1
]}

Debenham, Sheryl ^{[1
]}

Doebber, Thomas ^{[1
]}

Einstein, Monica ^{[1
]}

Liu, Kun ^{[1
]}

McCann, Margaret E. ^{[1
]}

Moller, David E. ^{[1
]}

Muise, Eric S. ^{[1
]}

Tan, Yugen ^{[1
]}

Thompson, John R. ^{[1
]}

Wong, Kenny K. ^{[1
]}

Wu, Margaret ^{[1
]}

Xu, Libo ^{[1
]}

Meinke, Peter T. ^{[1
]}

Berger, Joel P. ^{[1
]}

Wood, Harold B. ^{[1
]}

机构：

[1] Merck & Co Inc, Merck Res Labs, Rahway, NJ 07065 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 13期

关键词：

PPAR-GAMMA; BIOELECTRICAL-IMPEDANCE; PARTIAL AGONIST; DB/DB MICE; INSULIN; ROSIGLITAZONE; LIGANDS; RATS; THIAZOLIDINEDIONE; FRACTURES;

D O I：

10.1021/jm900097m

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

Peroxisome proliferator-activated receptor gamma (PPAR gamma) agonists are used to treat type 2 diabetes mellitus (T2DM). Widespread use of PPAR gamma agonists has been prevented due to adverse effects including weight gain, edema, and increased risk of congestive heart failure. Selective PPAR gamma modulators (SPPAR gamma Ms) have been identified that have antidiabetic efficacy and reduced toxicity in preclinical species. In comparison with PPAR gamma full agonists, SPPAR gamma M 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.

引用

页码：3846 / 3854

页数：9

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