2. Academic Validation
  3. 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 gamma modulator for the treatment of type 2 diabetes mellitus with a reduced potential to increase plasma and extracellular fluid volume

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 gamma modulator for the treatment of type 2 diabetes mellitus with a reduced potential to increase plasma and extracellular fluid volume

  • J Med Chem. 2009 Jul 9;52(13):3846-54. doi: 10.1021/jm900097m.
John J Acton 3rd 1,  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,  Yejun Tan,  John R Thompson,  Kenny K Wong,  Margaret Wu,  Libo Xu,  Peter T Meinke,  Joel P Berger,  Harold B Wood
Affiliations

Affiliation

  • 1 Merck Research Laboratories, Merck & Co., Inc., RY800-C114, Rahway, New Jersey 07065, USA.
PMID: 19507861 DOI: 10.1021/jm900097m
Abstract

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

Figures
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z