Activators of the nuclear orphan receptor peroxisome proliferato

Details Activators of the nuclear orphan receptor peroxisome proliferato Activators of the nuclear orphan receptor peroxisome proliferato

1998-02-25

1999-05-11

Gupta, Yogendra N.

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving antigen-antibody binding, specific binding protein...

424 169, 436518, 436536, 514342, 5462697, G01N33/53

Patent

active

059027266

ABSTRACT:
The present invention provides activator compounds, including agonists, to the peroxisome proliferator-activated receptor gamma. Particular PPAR.gamma. activators are set forth, as are a pharmaceutical composition for treating diabetes, non-insulin-dependent diabetes mellitus, cardiovascular disorders, and methods for such treatment.

REFERENCES:
patent: 5356913 (1994-10-01), Colca
J. Berger, et al., "Secreted Placental Alkaline Phosphatase: A Powerful New Quantitative Indicator of Gene Expression in Eukaryotic Cells," Gene, 66, pp. 1-10, 1988.
J.R. Colca and D.R. Morton, "Antihyperglycaemic Thiazolidinediones: Ciglitazone and Its Analogues," New Antibiotic Drugs, Chapter 24, pp. 255-261, Smith-Gordon, 1990.
A.Y. Chang, et al., "Ciglitazone, a New Hypoglycemic Agent. II. Effect on Glucose and Lipid Metabolisms and Insulin Binding in the Adipose Tissue of C57BL/6J-ob/ob and -+/? Mice," Diabetes, 32, pp. 839-845, Sep. 1983.
C. Dreyer, et al., "Control of the Peroxisomal .beta.-Oxidation Pathway by a Novel Family of Nuclear Hormone Receptors," Cell, pp. 879-887, Mar. 1992.
M. Gottlicher, et al., "Fatty Acids Activate a Chimera of the Clofibric Acid-Activated Receptor and the Glucocorticoid Receptor," Proc. Natl. Acad. Sci. USA, 89, pp. 4653-4657, May 1992.
R.A. Graves, et al., "Analysis of a Tissue-Specific Enhancer: ARF6 Regulates Adipogenic Gene Expression," Molecular and Cellular Biology, 12, No. 3, pp. 1202-1208, 1992.
P.K.W. Harris and R.F. Kletzien, "Localization of a Piolglitazone Response Element in the Adipocyte Fatty Acid-Binding Protein Gene," Molecular Pharmacology, 45, pp. 439-445, 1993.
A. Hiragun, et al., "Preadipocyte Differentiation in Vitro: Identification of a Highly Active Adipogenic Agent," J. of Cellular Physiology, 134, pp. 124-130, 1988.
A. Ibrahimi, et al., "Evidence for a Common Mechanism of Action for Fatty Acids and Thiazolidinedione Antidiabetic Agents on Gene Expresion in Preadipose Cells," Molecular Pharmacology, 46, pp. 1070-1076, 1994.
I. Issemann and S. Green, "Activation of a Member of the Steroid Hormone Receptor Superfamily by Peroxisome Proliferators," Nature, 347, pp. 645-650, 1990.
H. Keller and W. Wahli, "Peroxisome Proliferator-Activated Receptors," TEM, 4, No. 9, pp. 291-296, 1993.
R.F. Kletzien, et al., "Enhancement of Adipocyte Differentiation by an Insulin-Sensitizing Agent," Molecular Pharmacology, 41, pp. 393-398, 1992.
S.A. Kliewer, et al., "Differential Expression and Activation of a Family of Murine Peroxisome Proliferator-Activated Receptors," Proc. Natl. Acad. USA, 91, pp. 7355-7359, 1994.
B. Luckow and G. Schutz, "CAT Constructions with Multiple Unique Restriction Sites for the Functional Analysis of Eukaryotic Promoters and Regulatory Elements," Nucleic Acids Research, 15, No. 13, pp. 5490-5498, 1987.
D.J. Mangelsdorf, et al., "A Direct Repeat in the Cellular Retinol-Binding Protein Type II Gene Confers Differential Regulation by RXR and RAR," Cell, 66, pp. 555-561, Aug. 1991.
J.J. Nolan, et al., "Improvement in Glucose Tolerance and Insulin Resistance in Obese Subjects Treated with Troglitazone," New England J. of Med., 331, No. 18, pp. 1188-1193, Nov. 1994.
M. Pfahl, et al., "Nuclear Retinoic Acid Receptors: Cloning, Analysis, and Function," Methods in Enzymology, 189, pp. 256-270, 1990.
A. Schmidt, et al., "Identification of a New Member of the Steriod Hormone Receptor Superfamily That is Activated by a Peroxisome Proliferator and Fatty Acids," Molecular Endocrinology, 6, No. 4, pp. 1634-1641, 1992.
R.L. Sparks, et al., "Antidiabetic AD4743 Enhances Adipocyte Differentiation of 3T3 T Mesenchymal Stem Cells," J. of Cellular Physiology, 146, pp. 101-109, 1991.
P. Tontonoz, et al., "mPPAR.gamma.2: Tissue-Specific Regulator of an Adipocyte Enhancer," Genes & Development, 8, pp. 1224-1234, 1994.
Y. Zhu, et al., "Cloning of a New Member of the Peroxisome Proliferator-Activated Receptor Gene Family from Mouse Liver," J. of Biological Chem., 268, No. 36, pp. 26817-26820, 1993.
J. Berger, et al., Gene, 66, 1988, pp. 1-10, "Secreted Placental Alkaline Phosphatase: A Powerful New Quantitative Indicator of Gene Expression in Eukaryotic Cells".
J.R. Colca and D.R. Morton, New Antibiotic Drugs, Chapter 24, 1990, pp. 255-261, "Antihyperglycaemic Thiazolidinediones: Ciglitazone and Its Analogues".
A.Y. Chang, et al., Diabetes, vol. 32, Sep. 1983, pp. 839-845, "Ciglitazone, a New Hypoglycemic Agent. II Effect on Glucose and Lipid Metabolisms and Insulin Binding in the Adipose Tissue of C57BL/6J-ob/ob and -+/? Mice".
C. Dreyer, et al., Cell, vol. 68, Mar. 6, 1992, pp. 879-887, "Control of the Peroxisomal .beta.-Oxidation Pathway by a Novel Family of Nuclear Hormone Receptors".
M. Gottlicher, et al., Proc. Natl. Acad. Sci. USA. vol. 89, May 1992, pp. 4653-4657, "Fatty Acids Activate a Chimera of the Clofibric Acid-Activated Receptor and the Glucocorticoid Receptor".
R.A. Graves, et al., Molecular and Cellular Biology, vol. 12, No. 3, Mar. 1992, pp. 1202-1208, "Analysis of a Tissue-Specific Enhancer: ARF6 Regulates Adipogenic Gene Expression".
P.K.W. Harris and R.F. Kletzien, Molecular Pharmacology, 45, 1994, pp. 439-445, "Localization of a Pioglitazone Response Element in the Adipocyte Fatty Acid-Binding Protein Gene".
A. Hiragun, et al., Journal of Cellular Physiology, 134, 1988, pp. 124-130, "Preadipocyte Differentiation in Vitro: Identification of a Highly Active Adipogenic Agent".
A. Ibrahimi, et al., Molecular Pharmacology, 46, 1994, pp. 1070-1076, "Evidence for a Common Mechanism of Action for Fatty Acids and Thiazolidinedione Antidiabetic Agents on Gene Expression in Preadipose Cells".
I. Issemann and S. Green, Nature, vol. 347, Oct. 18, 1990, pp. 645-650, "Activation of a Member of the Steriod Hormone Receptor Superfamily by Peroxisome Proliferators".
H. Keller and W. Wahli, TEM, vol. 4, No. 9, 1993,pp. 291-296, "Peroxisome Proliferator-Activated Receptors".
R.F. Kletzien, et al., Molecular Pharmacology, 41, 1992, pp. 393-398, "Enhancement of Adipocyte Differentiation by an Insulin--Sensitizing Agent".
S.A. Kliewer, et al., Proc. Natl. Acad. Sci. USA, vol. 91, Jul. 1994, pp. 7355-7359, "Differential Expression and Activation of a Family of Murine Peroxisome Proliferator-Activated Receptors".
B. Luckow and G. Schutz, Nucleic Acids Research, vol.15 No. 13, 1987, p. 5490, "CAT Constructions with Multiple Unique Restriction Sites for the Functional Analysis of Eukaryotic Promoters and Regulatory Elements".
D.J. Mangelsdorf, et al., Cell, vol. 66, Aug. 9, 1991, pp. 555-561, " A Direct Repeat in the Cellular Retinol-Binding Protein Type II Gene Confers Differential Regulation by RXR and RAR".
J.J. Nolan, et al., The New England Journal of Medicine, vol. 331, No. 18, Nov. 3, 1994, pp. 1188-1193, "Improvement in Glucose Tolerance and Insulin Resistance in Obese Subjects Treated with Troglitazone".
M. Pfahl, et al., Methods in Enzymology, vol. 189, 1990, pp. 256-270, "Nuclear Retinoic Acid Receptors: Cloning, Analysis, and Function".
A. Schmidt, et al., Molecular Endocrinology, vol. 6, No. 4, 1992, pp. 1634-1641, "Identification of A New Member of the Steriod Hormone Receptor Superfamily That is Activated by a Peroxisome Proliferator and Fatty Acids".
R.L. Sparks, et al., Journal of Cellular Physiology, 146, 1991, pp. 101-109, "Antidiabetic AD4743 Enhances Adipocyte Differentiation of 3T3 T Mesenchymal Stem Cells".
P. Tontonoz, et al., Genes & Development,8, 1994, pp. 1224-1234, "mPPAR.gamma.2: Tissue-Specific Regulator of an Adipocyte Enhancer".
Y. Zhu, et al., Journal of Biological Chemistry, vol. 268, No. 36, 1993, pp. 26817-26820, "Cloning of a New Member of the Peroxisome Proliferator-Activated Receptor Gene Family from Mouse Liver".
Chawla, et al., Endocrinology, vol. 135, No. 2, 1994, pp. 798-800, "Peroxisome Proliferator-Activated Receptor (PPAR) .gamma.: Adipose-Predominant Expression and Introduction Early in Adipocyte Differentiation".
Tonotonoz, et al., Cell, vol. 79, Dec. 30, 1994, pp. 1147-1156, "Stimulation of Adipogenesis in Fibroblasts by PPAR.gamma.2, a Lipid-Activated Transcription Factor".
Tontonoz, et al., Nucleic Acids R

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