Identification and characterization of 4-chloro-N-(2- {[5-trifluoromethyl)- 2-pyridyl] sulfonyl} ethyl)benzamide (GSK3787), a selective and irreversible peroxisome proliferator-activated receptor δ (PPARδ) antagonist

Journal of Medicinal Chemistry

Volumn 53, Issue 4, 2010, Pages 1857-1861

  Shearer, Barry G ^a   Wiethe, Robert W ^a   Ashe, Adam ^a   Billin, Andrew N ^a   Way, James M ^a   Stanley, Thomas B ^a   Wagner, Craig D ^a   Xu, Robert X ^a   Leesnitzer, Lisa M ^a   Merrihew, Raymond V ^a   Shearer, Todd W ^a   Jeune, Michael R ^a   Ulrich, John C ^a   Wilison, Timothy M ^a  

^a GLAXOSMITHKLINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CARNITINE PALMITOYLTRANSFERASE I; CYSTEINE; GSK 3787; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ANTAGONIST; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR DELTA; PYRIDYLSULFONE; SULFONE; UNCLASSIFIED DRUG;

ARTICLE; CONTROLLED STUDY; DRUG BINDING; DRUG IDENTIFICATION; DRUG POTENCY; DRUG STRUCTURE; GENE EXPRESSION; GENETIC TRANSCRIPTION; HUMAN; HUMAN CELL; MASS SPECTROMETRY; PROTEIN BINDING;

ANIMALS; ANTINEOPLASTIC AGENTS; BENZAMIDES; BINDING SITES; CARNITINE O-PALMITOYLTRANSFERASE; CELL LINE, TUMOR; CYSTEINE; DRUG SCREENING ASSAYS, ANTITUMOR; GENES, REPORTER; HUMANS; LIGANDS; MALE; MASS SPECTROMETRY; MICE; MICE, INBRED C57BL; MUSCLE FIBERS, SKELETAL; PPAR DELTA; PROTEIN-SERINE-THREONINE KINASES; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONES; TISSUE DISTRIBUTION; TRANSCRIPTION, GENETIC;

EID: 77649208140     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm900464j     Document Type: Article

References (21)

1. Berger. J.: Moller, D. E. The Mechanisms of Action of PPARs. Annu. Rev. Med. 2002, 53, 409-435.
2. Staels, B.; Dallongeville, J.; Auwerx, J.; Schoonjans, K.; Leitersdorf, E.; Furchart, J.-C. Mechanism of Action of Fibrates on Lipid, and Lipoprotein Metabolism. Circulation 1998, 98, 2088-2093. (Pubitemid 28512236)
3. Spiegleman, B. M.; Flier, J. S. Adipogenesis and Obesity: Rounding Out the Big Picture. Cell. 1996, 87, 377-389.
4. Burdick, A. D.; Kim, D. J.; Peraza, M. A.; Gonzalez, F. J.; Peters, J. M. The role of Peroxisome-Activated Receptot-β/δ in Epithelial Cell Growth and. Differentiation. Cell. Signalling 2006, 18, 9-20.
5. Lopez-Soriano, J.; Chiellini, J.; Maffei, M.; Grimaldi, P. A.; Argiles, J. M. Roles of Skeletal Muscle and Peroxisome ProliferatorActivated Receptors in the Development and Treatment of Obesity. Endocr. Rev.- 2006, 27, 318-329.
6. (a) Sprecher, D. L.; Massien, C.; Pearce, G.; Billin, A. N.; Perlstein, I.; Wilison, T. M.; Hassall, D. G.; Ancellin, N.; Patterson, S. D.; Lobe, D. C.; Johnson, T. G. Triglyceride: High-Density Lipoprotein Cholesterol Effects in Healthy Subjects Administered a Peroxisome Proliferator Activated. Receptor δ Agonist. Arterioscler. Thromb,. Vasc. Biol. 2007, 27, 359-365.
7. (b)Risérus, U.; Sprecher, D.; Johnson, T.; Olson, E.; Hirschberg, S.; Liu, A.; Fang, Z.; Hegde, P.; Richards, D.; Sarov-Blat, L.; Strum, J. C.; Basu, S.; Cheeseman, J.; Fielding, B. A.; Humphreys, S. M.; Danoff, T.; Moore, N. R.; Murgatroyd, P.; O'Rahilly, S.; Sutton, P.; Wilison, T.; Hassall, D.; Frayn, K. N.; Karpe, F. Activation of Peroxisome Proliferator-Activated Receptor (PPAR)δ Promotes Reversal of Multiple Metabolic Abnormalities, Reduces Oxidative Stress, and Increases Fatty Acid Oxidation in Moderately Obese Men. Diabetes 2008, 57, 332-339.
8. Sauerberg, P.; Olsen, G. S.; Jeppesen, L.; Mogensen, J. P.; Pettersson, I.; Jeppesen, C. B.; Daugaard, J. R.; Galsgaard, E. D.; Ynddal, L.; Fleckner, J.; Panajotova, V.; Polivka, Z.; Pinera, P.; Havranek, M.; Wulff, E. M. Identification and Synthesis of a Novel Selective Partial PPARδ Agonist with Full Efficacy on Lipid. Metabolism in Vitro and in Vivo. J. Med. Chem. 2007, 50, 1495-1503.
9. Shearer, B. G.; Patel, H. S.; Billin, A. N.; Way, J. M.; Winegar, D. A.; Lambert, M. H.; Xu, R. X.; Leesnitzer, L. M.; Merrihew, R. V.; Huet, S.: Wilison, T. M. Discovery of a Novel Class of PPARδ Partial Agonists. Bioorg. Med. Chem. Lett. 2008, 18, 5018-5022.
10. Shearer, B. G.; Steger, D. J.; Way, J. M.; Stanley, T. B.; Lobe, D. C.; Grillot, D. A.; Iannone, M. A.; Lazar, M. A.; Willson, T. M.; Billin, A. N. Identification and Characterization, of a Selective Peroxisome-Activated Receptor β/δ (NR1C2) Antagonist. Mol. Endocrinol. 2008, 22, 523-529. (Pubitemid 351185947)
11. Brown, P. J.; Smith-Oliver, T. A.; Charifson, P. S.; Tomkinson, N. C. O.; Fivush, A. M.; Sternbach, D. D.; Wade, L. E.; Orband-Miller, L.; Parks, D. J.; Blanchard, S. G.; Kliewer, S. A.; Lehmann, J. M.; Wilison, T. M. Identification of Peroxisome ProliferatorActivated Receptor Ligands from a Biased Chemical Library. Chem. Biol. 1997, 4, 909-918.
12. Graham, R. A.; Goodwin, B.; Merrihew, R. V.; Krol, W. L.; LeCluyse, E. L. Cloning, Tissue Expression, and Regulation of Beagle Dog CYP4A Genes. Toxicol. Sci. 2006, 92, 356-367.
13. 11 except cells are incubated with, competing agonist GW501516 (human = 2 nM; mouse = 6 nM) prior to addition to compound plates.
14. Elbrech, A.; Chen, Y.; Adams, A.; Berger, J.; Griffin, P.; Klatt, T.; Zhang, B.; Menke, J.; Zhou, G.; Smith, R. G.; Moeller, D. E. L-764406 Is a Partial Agonist of Human Peroxisome ProliferatorActivated Receptor γ J. Biol Chem. 1999, 274, 7913-7922.
15. Leesnitzer, L. M.; Parks, D. J.; Bledsoe, R. K.; Cobb, J. E.; Collins, J. L.; Consler, T. G.; Davis, R. G.; Hull-Ryde, E. A.; Lenhard, J. M.; Patel, L.; Plunket, K. D.; Shenk, J. L.; Stimmel, J. B.; Therapontos, C.; Wilison, T. M.; Blanchard, S. G. Functional Consequences of Cysteine Modification, in the Ligand Binding Sites of Peroxisome Proliferator Activated. Receptors by GW9662. Biochemistry 2002, 41, 6640-6650.
16. Takahashi, S.; Tanaka, T.; Kodama, T.; Sakai, J. Peroxisome Proliferator-Activated Receptor δ (PPARaδ), a Novel Target Site for Drug Discovery in Metabolic Syndrome. Pharmacol. Res. 2006, 53, 501-507.
17. Sugden, M. C.; Holness, M. J. Recent Advances in Mechanisms Regulating Glucose Oxidation at the Level of the Pyruvate Dehydrogenase Complex by PDKs. Am. J. Physiol: Endocrinol. Metab. 2003, 284, E855-E862.
18. Wang, D.; Wang, H.; Guo, Y.; Ning, W.; Katkuri, S.; Wahli, W.; Desvergne, B.; Dey, S. K.; DuBois, R. N. Crosstalk between peroxisome proliferator- activated recqrtor δ and VEGF stimulates cancer progression, Proc. Natl. Acad. Sci U.S.A. 2006, 103, 19069-19074.
19. Wang, D.; DuBois, R. N. Inflammatory Mediators and Nuclear Receptor Signaling in Colorectal, Cancer. Cell Cycle 2007, 6, 682-685.
20. Peters, J. M.; Hollingshead, H. E.; Gonzalez, F. J. Role of Peroxisome-Proliferator-Activated. Receptor β/δ (PPARβ/δ) in Gastrointestinal Tract Function and Disease. Clin. Sci. 2008, 115, 107-127.
21. Cell proliferation assay details: Luo, L.; Carson, J. D.; Molnar, K. S.; Tuske, S. J.; Coales, S. J.; Hamuro, Y.; Sung, C.; Sudakin, V.; Auger, K. R.; Dhanak, D.; Jackson, J. R.; Huang, P. S.; Tummino, P. J.; Copeland, R. A. Conformation-Dependent Ligand. Regulation of ATP Hydrolysis by Human KSP: Activation of Basal Hydrolysis and Inhibition of Microtubule-Stimulated Hydrolysis by a Single, Small Molecule Modulator. J. Am. Chem. Soc. 2008, 130, 7584-7591.