PMID- 19507861
OWN - NLM
STAT- MEDLINE
DCOM- 20090812
LR  - 20181201
IS  - 1520-4804 (Electronic)
IS  - 0022-2623 (Linking)
VI  - 52
IP  - 13
DP  - 2009 Jul 9
TI  - Discovery of 
      (2R)-2-(3-3-[(4-Methoxyphenyl)carbonyl]-2-methyl-6-(trifluoromethoxy)-1H-indol-1-ylphenoxy)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.
PG  - 3846-54
LID - 10.1021/jm900097m [doi]
AB  - 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.
FAU - Acton, John J 3rd
AU  - Acton JJ 3rd
AD  - Merck Research Laboratories, Merck & Co., Inc., RY800-C114, Rahway, New Jersey 
      07065, USA.
FAU - Akiyama, Taro E
AU  - Akiyama TE
FAU - Chang, Ching H
AU  - Chang CH
FAU - Colwell, Lawrence
AU  - Colwell L
FAU - Debenham, Sheryl
AU  - Debenham S
FAU - Doebber, Thomas
AU  - Doebber T
FAU - Einstein, Monica
AU  - Einstein M
FAU - Liu, Kun
AU  - Liu K
FAU - McCann, Margaret E
AU  - McCann ME
FAU - Moller, David E
AU  - Moller DE
FAU - Muise, Eric S
AU  - Muise ES
FAU - Tan, Yejun
AU  - Tan Y
FAU - Thompson, John R
AU  - Thompson JR
FAU - Wong, Kenny K
AU  - Wong KK
FAU - Wu, Margaret
AU  - Wu M
FAU - Xu, Libo
AU  - Xu L
FAU - Meinke, Peter T
AU  - Meinke PT
FAU - Berger, Joel P
AU  - Berger JP
FAU - Wood, Harold B
AU  - Wood HB
LA  - eng
PT  - Journal Article
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Indoles)
RN  - 0 (PPAR gamma)
RN  - 0 (Thiazolidinediones)
RN  - 05V02F2KDG (Rosiglitazone)
RN  - X4OV71U42S (Pioglitazone)
SB  - IM
EIN - J Med Chem. 2013 Nov 27;56(22):9368. Tan, Yugen [corrected to Tan, Yejun]
MH  - Animals
MH  - Blood Volume/drug effects
MH  - Body Fluids/drug effects
MH  - Diabetes Mellitus, Type 2/*drug therapy
MH  - Dogs
MH  - Haplorhini
MH  - Humans
MH  - Hypoglycemic Agents/adverse effects/*pharmacokinetics/therapeutic use
MH  - Indoles/adverse effects/*pharmacokinetics/therapeutic use
MH  - PPAR gamma/*agonists
MH  - Pioglitazone
MH  - Rats
MH  - Rosiglitazone
MH  - Structure-Activity Relationship
MH  - Thiazolidinediones
EDAT- 2009/06/11 09:00
MHDA- 2009/08/13 09:00
CRDT- 2009/06/11 09:00
PHST- 2009/06/11 09:00 [entrez]
PHST- 2009/06/11 09:00 [pubmed]
PHST- 2009/08/13 09:00 [medline]
AID - 10.1021/jm900097m [doi]
PST - ppublish
SO  - J Med Chem. 2009 Jul 9;52(13):3846-54. doi: 10.1021/jm900097m.