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

John J. Acton; 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. Thompson; Kenny K. Wong; Margaret Wu; Libo Xu; Peter T. Meinke; Joel P. Berger; Harold B. Wood

doi:10.1021/jm900097m

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

John J. Acton, 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. Thompson, Kenny K. Wong, Margaret Wu, Libo Xu, Peter T. Meinke, Joel P. Berger, Harold B. Wood

Department of Chemistry and Chemical Biology

Research output: Contribution to journal › Article › peer-review

47 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	3846-3854
Number of pages	9
Journal	Journal of Medicinal Chemistry
Volume	52
Issue number	13
DOIs	https://doi.org/10.1021/jm900097m
State	Published - 9 Jul 2009

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Acton, J. J., Akiyama, T. E., Chang, C. H., Colwell, L., Debenham, S., Doebber, T., Einstein, M., Liu, K., McCann, M. E., Moller, D. E., Muise, E. S., Tan, Y., Thompson, J. R., Wong, K. K., Wu, M., Xu, L., Meinke, P. T., Berger, J. P., & Wood, H. B. (2009). 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. Journal of Medicinal Chemistry, 52(13), 3846-3854. https://doi.org/10.1021/jm900097m

Acton, John J. ; Akiyama, Taro E. ; Chang, Ching H. et al. / 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. In: Journal of Medicinal Chemistry. 2009 ; Vol. 52, No. 13. pp. 3846-3854.

@article{841c1aba9e6a4fbf96e4dd2b27fbde4b,

title = "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",

abstract = "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.",

author = "Acton, {John J.} and Akiyama, {Taro E.} and Chang, {Ching H.} and Lawrence Colwell and Sheryl Debenham and Thomas Doebber and Monica Einstein and Kun Liu and McCann, {Margaret E.} and Moller, {David E.} and Muise, {Eric S.} and Yugen Tan and Thompson, {John R.} and Wong, {Kenny K.} and Margaret Wu and Libo Xu and Meinke, {Peter T.} and Berger, {Joel P.} and Wood, {Harold B.}",

year = "2009",

month = jul,

day = "9",

doi = "10.1021/jm900097m",

language = "English",

volume = "52",

pages = "3846--3854",

number = "13",

}

Acton, JJ, Akiyama, TE, Chang, CH, Colwell, L, Debenham, S, Doebber, T, Einstein, M, Liu, K, McCann, ME, Moller, DE, Muise, ES, Tan, Y, Thompson, JR, Wong, KK, Wu, M, Xu, L, Meinke, PT, Berger, JP & Wood, HB 2009, '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', Journal of Medicinal Chemistry, vol. 52, no. 13, pp. 3846-3854. https://doi.org/10.1021/jm900097m

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. / Acton, John J.; Akiyama, Taro E.; Chang, Ching H. et al.
In: Journal of Medicinal Chemistry, Vol. 52, No. 13, 09.07.2009, p. 3846-3854.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Discovery of (2R)-2-(3-{3-[(4-methoxyphenyl)carbonyl]-2-methyl-6- (trifluoromethoxy)-1H-indol-1-yl}phenoxy)butanoic acid (MK-0533)

T2 - 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

AU - Acton, John J.

AU - Akiyama, Taro E.

AU - Chang, Ching H.

AU - Colwell, Lawrence

AU - Debenham, Sheryl

AU - Doebber, Thomas

AU - Einstein, Monica

AU - Liu, Kun

AU - McCann, Margaret E.

AU - Moller, David E.

AU - Muise, Eric S.

AU - Tan, Yugen

AU - Thompson, John R.

AU - Wong, Kenny K.

AU - Wu, Margaret

AU - Xu, Libo

AU - Meinke, Peter T.

AU - Berger, Joel P.

AU - Wood, Harold B.

PY - 2009/7/9

Y1 - 2009/7/9

N2 - 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.

AB - 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.

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U2 - 10.1021/jm900097m

DO - 10.1021/jm900097m

M3 - Article

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SN - 0022-2623

VL - 52

SP - 3846

EP - 3854

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 13

ER -

Acton JJ, Akiyama TE, Chang CH, Colwell L, Debenham S, Doebber T et al. 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. Journal of Medicinal Chemistry. 2009 Jul 9;52(13):3846-3854. doi: 10.1021/jm900097m

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