Peroxisome Proliferator-Activated Receptor γ (PPARγ) and Ligand Choreography: Newcomers Take the Stage

Journal of Medicinal Chemistry

Volumn 58, Issue 14, 2015, Pages 5381-5394

  Garcia Vallvé, Santiago ^a,b   Guasch, Laura ^c   Tomas Hernández, Sarah ^a   Del Bas, Josep Maria ^b   Ollendorff, Vincent ^d   Arola, Lluís ^a,b   Pujadas, Gerard ^a,b   Mulero, Miquel ^a  

^a UNIVERSITAT ROVIRA I VIRGILI   (Spain)

^b Avinguda Universitat   (Spain)

^c NATIONAL CANCER INSTITUTE   (United States)

^d University of Montpellier   (France)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIDIABETIC AGENT; LIGAND; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR AGONIST; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; SERINE;

ARTICLE; BINDING AFFINITY; DRUG BINDING SITE; DRUG RECEPTOR BINDING; DRUG SCREENING; DRUG STRUCTURE; GENOMICS; HUMAN; NONHUMAN; PROTEIN PHOSPHORYLATION; AGONISTS; ANIMAL; ANTAGONISTS AND INHIBITORS; CHEMISTRY; DRUG DEVELOPMENT; DRUG EFFECTS; METABOLISM; PHOSPHORYLATION; STRUCTURE ACTIVITY RELATION;

ANIMALS; DRUG DISCOVERY; HUMANS; HYPOGLYCEMIC AGENTS; LIGANDS; PHOSPHORYLATION; PPAR GAMMA; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84937678772     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm501155f     Document Type: Article

References (80)

1. Berger, J.; Moller, D. E. The Mechanisms of Action of PPARs Annu. Rev. Med. 2002, 53, 409-435
2. Lehmann, J. M.; Moore, L. B.; Smith-Oliver, T. A.; Wilkison, W. O.; Willson, T. M.; Kliewer, S. A. An Antidiabetic Thiazolidinedione Is a High Affinity Ligand for Peroxisome Proliferator-Activated Receptor (PPAR) J. Biol. Chem. 1995, 270, 12953-12956
3. Feldman, P.; Lambert, M.; Henke, B. PPAR Modulators and PPAR Pan Agonists for Metabolic Diseases: The Next Generation of Drugs Targeting Peroxisome Proliferator-Activated Receptors? Curr. Top. Med. Chem. 2008, 8, 728-749
4. Pourcet, B.; Fruchart, J.-C.; Staels, B.; Glineur, C. Selective PPAR Modulators, Dual and Pan PPAR Agonists: Multimodal Drugs for the Treatment of Type 2 Diabetes and Atherosclerosis Expert Opin. Emerging Drugs 2006, 11, 379-401
5. Jones, D. Potential Remains for PPAR-Targeted Drugs Nat. Rev. Drug Discovery 2010, 9, 668-669
6. Germain, P.; Staels, B.; Dacquet, C.; Spedding, M.; Laudet, V. Overview of Nomenclature of Nuclear Receptors Pharmacol. Rev. 2006, 58, 685-704
7. Kojetin, D. J.; Burris, T. P. Small Molecule Modulation of Nuclear Receptor Conformational Dynamics: Implications for Function and Drug Discovery Mol. Pharmacol. 2013, 83, 1-8
8. Bruning, J. B.; Chalmers, M. J.; Prasad, S.; Busby, S. A.; Kamenecka, T. M.; He, Y.; Nettles, K. W.; Griffin, P. R. Partial Agonists Activate PPARγ Using a Helix 12 Independent Mechanism Structure 2007, 15, 1258-1271
9. Hughes, T. S.; Chalmers, M. J.; Novick, S.; Kuruvilla, D. S.; Chang, M. R.; Kamenecka, T. M.; Rance, M.; Johnson, B. A.; Burris, T. P.; Griffin, P. R.; Kojetin, D. J. Ligand and Receptor Dynamics Contribute to the Mechanism of Graded PPARγ Agonism Structure 2012, 20, 139-150
10. Nielsen, R.; Pedersen, T. A.; Hagenbeek, D.; Moulos, P.; Siersbaek, R.; Megens, E.; Denissov, S.; Børgesen, M.; Francoijs, K.-J.; Mandrup, S.; Stunnenberg, H. G. Genome-Wide Profiling of PPARgamma:RXR and RNA Polymerase II Occupancy Reveals Temporal Activation of Distinct Metabolic Pathways and Changes in RXR Dimer Composition during Adipogenesis Genes Dev. 2008, 22, 2953-2967
11. Haakonsson, A. K.; Stahl Madsen, M.; Nielsen, R.; Sandelin, A.; Mandrup, S. Acute Genome-Wide Effects of Rosiglitazone on PPARγ Transcriptional Networks in Adipocytes Mol. Endocrinol. 2013, 27, 1536-1549
12. Lefterova, M. I.; Haakonsson, A. K.; Lazar, M. A.; Mandrup, S. PPARγ and the Global Map of Adipogenesis and Beyond Trends Endocrinol. Metab. 2014, 25, 293-302
13. Bortolini, M.; Wright, M. B.; Bopst, M.; Balas, B. Examining the Safety of PPAR Agonists-Current Trends and Future Prospects Expert Opin. Drug Saf. 2013, 12, 65-79
14. Gelman, L.; Feige, J. N.; Desvergne, B. Molecular Basis of Selective PPARgamma Modulation for the Treatment of Type 2 Diabetes Biochim. Biophys. Acta 2007, 1771, 1094-1107
15. Pirat, C.; Farce, A.; Lebègue, N.; Renault, N.; Furman, C.; Millet, R.; Yous, S.; Speca, S.; Berthelot, P.; Desreumaux, P.; Chavatte, P. Targeting Peroxisome Proliferator-Activated Receptors (PPARs): Development of Modulators J. Med. Chem. 2012, 55, 4027-4061
16. Farce, A.; Renault, N.; Chavatte, P. Structural Insight into PPARgamma Ligands Binding Curr. Med. Chem. 2009, 16, 1768-1789
17. Guasch, L.; Sala, E.; Valls, C.; Blay, M.; Mulero, M.; Arola, L.; Pujadas, G.; Garcia-Vallvé, S. Structural Insights for the Design of New PPARgamma Partial Agonists with High Binding Affinity and Low Transactivation Activity J. Comput.-Aided Mol. Des. 2011, 25, 717-728
18. Zoete, V.; Grosdidier, A.; Michielin, O. Peroxisome Proliferator-Activated Receptor Structures: Ligand Specificity, Molecular Switch and Interactions with Regulators Biochim. Biophys. Acta, Mol. Cell Biol. Lipids 2007, 1771, 915-925
19. Pochetti, G.; Godio, C.; Mitro, N.; Caruso, D.; Galmozzi, A.; Scurati, S.; Loiodice, F.; Fracchiolla, G.; Tortorella, P.; Laghezza, A.; Lavecchia, A.; Novellino, E.; Mazza, F.; Crestani, M. Insights into the Mechanism of Partial Agonism: Crystal Structures of the Peroxisome Proliferator-Activated Receptor Gamma Ligand-Binding Domain in the Complex with Two Enantiomeric Ligands J. Biol. Chem. 2007, 282, 17314-17324
20. Renaud, J. P.; Rochel, N.; Ruff, M.; Vivat, V.; Chambon, P.; Gronemeyer, H.; Moras, D. Crystal Structure of the RAR-γ Ligand-Binding Domain Bound to All-Trans Retinoic Acid Nature 1995, 378, 681-689
21. Aranda, A.; Pascual, A. Nuclear Hormone Receptors and Gene Expression Physiol. Rev. 2001, 81, 1269-1304
22. Choi, J. H.; Banks, A. S.; Estall, J. L.; Kajimura, S.; Boström, P.; Laznik, D.; Ruas, J. L.; Chalmers, M. J.; Kamenecka, T. M.; Blüher, M.; Griffin, P. R.; Spiegelman, B. M. Anti-Diabetic Drugs Inhibit Obesity-Linked Phosphorylation of PPARgamma by Cdk5 Nature 2010, 466, 451-456
23. Rieusset, J.; Touri, F.; Michalik, L.; Escher, P.; Desvergne, B.; Niesor, E.; Wahli, W. A New Selective Peroxisome Proliferator-Activated Receptor Gamma Antagonist with Antiobesity and Antidiabetic Activity Mol. Endocrinol. 2002, 16, 2628-2644
24. Doggrell, S. Do Peroxisome Proliferation Receptor-Gamma Antagonists Have Clinical Potential as Combined Antiobesity and Antidiabetic Drugs? Expert Opin. Invest. Drugs 2003, 12, 713-716
25. Mukherjee, R.; Hoener, P. A.; Jow, L.; Bilakovics, J.; Klausing, K.; Mais, D. E.; Faulkner, A.; Croston, G. E.; Paterniti, J. R. A Selective Peroxisome Proliferator-Activated Receptor-Gamma (PPARgamma) Modulator Blocks Adipocyte Differentiation but Stimulates Glucose Uptake in 3T3-L1 Adipocytes Mol. Endocrinol. 2000, 14, 1425-1433
26. Choi, J. H.; Banks, A. S.; Kamenecka, T. M.; Busby, S. A.; Chalmers, M. J.; Kumar, N.; Kuruvilla, D. S.; Shin, Y.; He, Y.; Bruning, J. B.; Marciano, D. P.; Cameron, M. D.; Laznik, D.; Jurczak, M. J.; Schürer, S. C.; Vidović, D.; Shulman, G. I.; Spiegelman, B. M.; Griffin, P. R. Antidiabetic Actions of a Non-Agonist PPARγ Ligand Blocking Cdk5-Mediated Phosphorylation Nature 2011, 477, 477-481
27. Corzo, C.; Griffin, P. R. Targeting the Peroxisome Proliferator-Activated Receptor-γ Tto Counter the Inflammatory Milieu in Obesity Diabetes Metab. J. 2013, 37, 395-403
28. Lee, H.-M.; Lee, O.-H.; Lee, B.-Y. Effect of Ginsenoside Rg3 and Rh2 on Glucose Uptake in Insulin-Resistant Muscle Cells J. Korean Soc. Appl. Biol. Chem. 2010, 53, 106-109
29. Gong, Z.; Huang, C.; Sheng, X.; Zhang, Y.; Li, Q.; Wang, M.-W.; Peng, L.; Zang, Y. Q. The Role of Tanshinone IIA in the Treatment of Obesity through Peroxisome Proliferator-Activated Receptor Gamma Antagonism Endocrinology 2009, 150, 104-113
30. Choi, J. H.; Choi, S.-S.; Kim, E. S.; Jedrychowski, M. P.; Yang, Y. R.; Jang, H.-J.; Suh, P.-G.; Banks, A. S.; Gygi, S. P.; Spiegelman, B. M. Thrap3 Docks on Phosphoserine 273 of PPARγ and Controls Diabetic Gene Programming Genes Dev. 2014, 28, 2361-2369
31. Houtkooper, R. H.; Auwerx, J. Obesity: New Life for Antidiabetic Drugs Nature 2010, 466, 443-444
32. Kahn, B. B.; McGraw, T. E. Rosiglitazone, PPARγ, and Type 2 Diabetes N. Engl. J. Med. 2010, 363, 2667-2669
33. Grether, U.; Klaus, W.; Kuhn, B.; Maerki, H. P.; Mohr, P.; Wright, M. B. New Insights on the Mechanism of PPAR-Targeted Drugs ChemMedChem 2010, 5, 1973-1976
34. Whitehead, J. P. Diabetes: New Conductors for the Peroxisome Proliferator-Activated Receptor γ (PPARγ) Orchestra Int. J. Biochem. Cell Biol. 2011, 43, 1071-1074
35. Wilson, C. Diabetes: T2DM-PPARγ Ligands without the Adverse Effects? Nat. Rev. Endocrinol. 2011, 7, 630
36. Crunkhorn, S. Diabetes: Safer PPARγ-Targeted Drugs on the Horizon? Nat. Rev. Drug Discovery 2011, 10, 814
37. Choi, S.-S.; Kim, E. S.; Koh, M.; Lee, S.-J.; Lim, D.; Yang, Y. R.; Jang, H.-J.; Seo, K.-A.; Min, S.-H.; Lee, I. H.; Park, S. B.; Suh, P.-G.; Choi, J. H. A Novel Non-Agonist Peroxisome Proliferator-Activated Receptor γ (PPARγ) Ligand UHC1 Blocks PPARγ Phosphorylation by Cyclin-Dependent Kinase 5 (CDK5) and Improves Insulin Sensitivity J. Biol. Chem. 2014, 289, 26618-26629
38. Kouskoumvekaki, I.; Petersen, R. K.; Fratev, F.; Taboureau, O.; Nielsen, T. E.; Oprea, T. I.; Sonne, S. B.; Flindt, E. N.; Jónsdóttir, S. Ó.; Kristiansen, K. Discovery of a Novel Selective PPARγ Ligand with Partial Agonist Binding Properties by Integrated in Silico/in Vitro Work Flow J. Chem. Inf. Model. 2013, 53, 923-937
39. Amato, A. A.; Rajagopalan, S.; Lin, J. Z.; Carvalho, B. M.; Figueira, A. C. M.; Lu, J.; Ayers, S. D.; Mottin, M.; Silveira, R. L.; Souza, P. C. T.; Mourão, R. H. V; Saad, M. J. A.; Togashi, M.; Simeoni, L. A.; Abdalla, D. S. P.; Skaf, M. S.; Polikparpov, I.; Lima, M. C. A.; Galdino, S. L.; Brennan, R. G.; Baxter, J. D.; Pitta, I. R.; Webb, P.; Phillips, K. J.; Neves, F. A. R. GQ-16, a Novel Peroxisome Proliferator-Activated Receptor γ (PPARγ) Ligand, Promotes Insulin Sensitization without Weight Gain J. Biol. Chem. 2012, 287, 28169-28179
40. Liu, J.; Ormö, M.; Nyström, A.-C.; Claesson, J.; Giordanetto, F. Transient Expression, Purification and Characterisation of Human Full-Length PPARγ2 in HEK293 Cells Protein Expression Purif. 2013, 89, 189-195
41. Koh, M.; Park, J.; Koo, J. Y.; Lim, D.; Cha, M. Y.; Jo, A.; Choi, J. H.; Park, S. B. Phenotypic Screening To Identify Small-Molecule Enhancers for Glucose Uptake: Target Identification and Rational Optimization of Their Efficacy Angew. Chem., Int. Ed. 2014, 53, 5102-5106
42. Liberato, M. V.; Nascimento, A. S.; Ayers, S. D.; Lin, J. Z.; Cvoro, A.; Silveira, R. L.; Martinez, L.; Souza, P. C. T.; Saidemberg, D.; Deng, T.; Amato, A. A.; Togashi, M.; Hsueh, W. A.; Phillips, K.; Palma, M. S.; Neves, F. A. R.; Skaf, M. S.; Webb, P.; Polikarpov, I. Medium Chain Fatty Acids Are Selective Peroxisome Proliferator Activated Receptor (PPAR) γ Activators and Pan-PPAR Partial Agonists PLoS One 2012, 7, e36297
43. Zheng, W.; Feng, X.; Qiu, L.; Pan, Z.; Wang, R.; Lin, S.; Hou, D.; Jin, L.; Li, Y. Identification of the Antibiotic Ionomycin as an Unexpected Peroxisome Proliferator-Activated Receptor γ (PPARγ) Ligand with a Unique Binding Mode and Effective Glucose-Lowering Activity in a Mouse Model of Diabetes Diabetologia 2013, 56, 401-411
44. Benson, S. C.; Pershadsingh, H. A.; Ho, C. I.; Chittiboyina, A.; Desai, P.; Pravenec, M.; Qi, N.; Wang, J.; Avery, M. A.; Kurtz, T. W. Identification of Telmisartan as a Unique Angiotensin II Receptor Antagonist with Selective PPARgamma-Modulating Activity Hypertension 2004, 43, 993-1002
45. Wu, G.; Yi, J.; Liu, L.; Wang, P.; Zhang, Z.; Li, Z. Pseudoginsenoside F11, a Novel Partial PPAR γ Agonist, Promotes Adiponectin Oligomerization and Secretion in 3T3-L1 Adipocytes PPAR Res. 2013, 2013, 701017
46. Weidner, C.; de Groot, J. C.; Prasad, A.; Freiwald, A.; Quedenau, C.; Kliem, M.; Witzke, A.; Kodelja, V.; Han, C.-T.; Giegold, S.; Baumann, M.; Klebl, B.; Siems, K.; Müller-Kuhrt, L.; Schürmann, A.; Schüler, R.; Pfeiffer, A. F. H.; Schroeder, F. C.; Büssow, K.; Sauer, S. Amorfrutins Are Potent Antidiabetic Dietary Natural Products Proc. Natl. Acad. Sci. U.S.A. 2012, 109, 7257-7262
47. Zhang, N.; Chen, W.; Zhou, X.; Zhou, X.; Xie, X.; Meng, A.; Li, S.; Wang, L. C333H Ameliorated Insulin Resistance through Selectively Modulating Peroxisome Proliferator-Activated Receptor γ in Brown Adipose Tissue of db/db Mice Biol. Pharm. Bull. 2013, 36, 980-987
48. Weidner, C.; Wowro, S. J.; Freiwald, A.; Kawamoto, K.; Witzke, A.; Kliem, M.; Siems, K.; Müller-Kuhrt, L.; Schroeder, F. C.; Sauer, S. Amorfrutin B Is an Efficient Natural Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) Agonist with Potent Glucose-Lowering Properties Diabetologia 2013, 56, 1802-1812
49. Malapaka, R. R. V; Khoo, S.; Zhang, J.; Choi, J. H.; Zhou, X. E.; Xu, Y.; Gong, Y.; Li, J.; Yong, E.-L.; Chalmers, M. J.; Chang, L.; Resau, J. H.; Griffin, P. R.; Chen, Y. E.; Xu, H. E. Identification and Mechanism of 10-Carbon Fatty Acid as Modulating Ligand of Peroxisome Proliferator-Activated Receptors J. Biol. Chem. 2012, 287, 183-195
50. Hughes, T. S.; Giri, P. K.; de Vera, I. M. S.; Marciano, D. P.; Kuruvilla, D. S.; Shin, Y.; Blayo, A.-L.; Kamenecka, T. M.; Burris, T. P.; Griffin, P. R.; Kojetin, D. J. An Alternate Binding Site for PPARγ Ligands Nat. Commun. 2014, 5, 3571
51. Hamza, M. S.; Pott, S.; Vega, V. B.; Thomsen, J. S.; Kandhadayar, G. S.; Ng, P. W. P.; Chiu, K. P.; Pettersson, S.; Wei, C. L.; Ruan, Y.; Liu, E. T. De-Novo Identification of PPARgamma/RXR Binding Sites and Direct Targets during Adipogenesis PLoS One 2009, 4, e4907
52. Wakabayashi, K.; Okamura, M.; Tsutsumi, S.; Nishikawa, N. S.; Tanaka, T.; Sakakibara, I.; Kitakami, J.; Ihara, S.; Hashimoto, Y.; Hamakubo, T.; Kodama, T.; Aburatani, H.; Sakai, J. The Peroxisome Proliferator-Activated Receptor Gamma/Retinoid X Receptor Alpha Heterodimer Targets the Histone Modification Enzyme PR-Set7/Setd8 Gene and Regulates Adipogenesis through a Positive Feedback Loop Mol. Cell. Biol. 2009, 29, 3544-3555
53. Lefterova, M. I.; Zhang, Y.; Steger, D. J.; Schupp, M.; Schug, J.; Cristancho, A.; Feng, D.; Zhuo, D.; Stoeckert, C. J.; Liu, X. S.; Lazar, M. A. PPARgamma and C/EBP Factors Orchestrate Adipocyte Biology via Adjacent Binding on a Genome-Wide Scale Genes Dev. 2008, 22, 2941-2952
54. Lefterova, M. I.; Steger, D. J.; Zhuo, D.; Qatanani, M.; Mullican, S. E.; Tuteja, G.; Manduchi, E.; Grant, G. R.; Lazar, M. A. Cell-Specific Determinants of Peroxisome Proliferator-Activated Receptor Gamma Function in Adipocytes and Macrophages Mol. Cell. Biol. 2010, 30, 2078-2089
55. Pott, S.; Kamrani, N. K.; Bourque, G.; Pettersson, S.; Liu, E. T. PPARG Binding Landscapes in Macrophages Suggest a Genome-Wide Contribution of PU.1 to Divergent PPARG Binding in Human and Mouse PLoS One 2012, 7, e48102
56. Yu, S.; Xu, H. E. Couple Dynamics: PPARγ and Its Ligand Partners Structure 2012, 20, 2-4
57. Ahmadian, M.; Suh, J. M.; Hah, N.; Liddle, C.; Atkins, A. R.; Downes, M.; Evans, R. M. PPARγ Signaling and Metabolism: The Good, the Bad and the Future Nat. Med. 2013, 19, 557-566
58. Nolte, R. T.; Wisely, G. B.; Westin, S.; Cobb, J. E.; Lambert, M. H.; Kurokawa, R.; Rosenfeld, M. G.; Willson, T. M.; Glass, C. K.; Milburn, M. V. Ligand Binding and Co-Activator Assembly of the Peroxisome Proliferator-Activated Receptor-Gamma Nature 1998, 395, 137-143
59. Chandra, V.; Huang, P.; Hamuro, Y.; Raghuram, S.; Wang, Y.; Burris, T. P.; Rastinejad, F. Structure of the Intact PPAR-Gamma-RXR-Nuclear Receptor Complex on DNA Nature 2008, 456, 350-356
60. Banks, A. S.; McAllister, F. E.; Camporez, J. P. G.; Zushin, P.-J. H.; Jurczak, M. J.; Laznik-Bogoslavski, D.; Shulman, G. I.; Gygi, S. P.; Spiegelman, B. M. An ERK/Cdk5 Axis Controls the Diabetogenic Actions of PPARγ Nature 2015, 517, 391-395
61. Zhao, Y.; Huang, Y.; He, J.; Li, C.; Deng, W.; Ran, X.; Wang, D. Rosiglitazone, a Peroxisome Proliferator-Activated Receptor-γ Agonist, Attenuates Airway Inflammation by Inhibiting the Proliferation of Effector T Cells in a Murine Model of Neutrophilic Asthma Immunol. Lett. 2014, 157, 9-15
62. Mastrofrancesco, A.; Kovacs, D.; Sarra, M.; Bastonini, E.; Cardinali, G.; Aspite, N.; Camera, E.; Chavatte, P.; Desreumaux, P.; Monteleone, G.; Picardo, M. Preclinical Studies of a Specific PPARγ Modulator in the Control of Skin Inflammation J. Invest. Dermatol. 2014, 134, 1001-1011
63. Grommes, C.; Landreth, G. E.; Heneka, M. T. Antineoplastic Effects of Peroxisome Proliferator-Activated Receptor Gamma Agonists Lancet Oncol. 2004, 5, 419-429
64. Jia, Z.; Sun, Y.; Yang, G.; Zhang, A.; Huang, S.; Heiney, K. M.; Zhang, Y. New Insights into the PPARγ Agonists for the Treatment of Diabetic Nephropathy PPAR Res. 2014, 2014, 818530
65. Le Foll, B.; Di Ciano, P.; Panlilio, L. V.; Goldberg, S. R.; Ciccocioppo, R. Peroxisome Proliferator-Activated Receptor (PPAR) Agonists as Promising New Medications for Drug Addiction: Preclinical Evidence Curr. Drug Targets 2013, 14, 768-776
66. Tailleux, A.; Wouters, K.; Staels, B. Roles of PPARs in NAFLD: Potential Therapeutic Targets Biochim. Biophys. Acta 2012, 1821, 809-818
67. Heneka, M. T.; Reyes-Irisarri, E.; Hüll, M.; Kummer, M. P. Impact and Therapeutic Potential of PPARs in Alzheimer's Disease Curr. Neuropharmacol. 2011, 9, 643-650
68. Carta, A. R.; Pisanu, A.; Carboni, E. Do PPAR-Gamma Agonists Have a Future in Parkinson's Disease Therapy? Parkinson's Dis. 2011, 2011, 689181
69. Pascual, G.; Fong, A. L.; Ogawa, S.; Gamliel, A.; Li, A. C.; Perissi, V.; Rose, D. W.; Willson, T. M.; Rosenfeld, M. G.; Glass, C. K. A SUMOylation-Dependent Pathway Mediates Transrepression of Inflammatory Response Genes by PPAR-Gamma Nature 2005, 437, 759-763
70. Marciano, D. P.; Chang, M. R.; Corzo, C. A.; Goswami, D.; Lam, V. Q.; Pascal, B. D.; Griffin, P. R. The Therapeutic Potential of Nuclear Receptor Modulators for Treatment of Metabolic Disorders: PPARγ, RORs, and Rev-Erbs Cell Metab. 2014, 19, 193-208
71. Ohno, H.; Shinoda, K.; Spiegelman, B. M.; Kajimura, S. PPARγ Agonists Induce a White-to-Brown Fat Conversion through Stabilization of PRDM16 Protein Cell Metab. 2012, 15, 395-404
72. Chen, Z.; Vigueira, P. A.; Chambers, K. T.; Hall, A. M.; Mitra, M. S.; Qi, N.; McDonald, W. G.; Colca, J. R.; Kletzien, R. F.; Finck, B. N. Insulin Resistance and Metabolic Derangements in Obese Mice Are Ameliorated by a Novel Peroxisome Proliferator-Activated Receptor γ-Sparing Thiazolidinedione J. Biol. Chem. 2012, 287, 23537-23548
73. Colca, J. R.; Tanis, S. P.; McDonald, W. G.; Kletzien, R. F. Insulin Sensitizers in 2013: New Insights for the Development of Novel Therapeutic Agents to Treat Metabolic Diseases Expert Opin. Invest. Drugs 2014, 23, 1-7
74. Gregoire, F. M.; Zhang, F.; Clarke, H. J.; Gustafson, T. A.; Sears, D. D.; Favelyukis, S.; Lenhard, J.; Rentzeperis, D.; Clemens, L. E.; Mu, Y.; Lavan, B. E. MBX-102/JNJ39659100, a Novel Peroxisome Proliferator-Activated Receptor-Ligand with Weak Transactivation Activity Retains Antidiabetic Properties in the Absence of Weight Gain and Edema Mol. Endocrinol. 2009, 23, 975-988
75. Ostberg, T.; Svensson, S.; Selén, G.; Uppenberg, J.; Thor, M.; Sundbom, M.; Sydow-Bäckman, M.; Gustavsson, A.-L.; Jendeberg, L. A New Class of Peroxisome Proliferator-Activated Receptor Agonists with a Novel Binding Epitope Shows Antidiabetic Effects J. Biol. Chem. 2004, 279, 41124-41130
76. Lamotte, Y.; Martres, P.; Faucher, N.; Laroze, A.; Grillot, D.; Ancellin, N.; Saintillan, Y.; Beneton, V.; Gampe, R. T. Synthesis and Biological Activities of Novel Indole Derivatives as Potent and Selective PPARgamma Modulators Bioorg. Med. Chem. Lett. 2010, 20, 1399-1404
77. Acton, J. J.; Black, R. M.; Jones, A. B.; Moller, D. E.; Colwell, L.; Doebber, T. W.; Macnaul, K. L.; Berger, J.; Wood, H. B. Benzoyl 2-Methyl Indoles as Selective PPARgamma Modulators Bioorg. Med. Chem. Lett. 2005, 15, 357-362
78. Kolli, V.; Stechschulte, L. A.; Dowling, A. R.; Rahman, S.; Czernik, P. J.; Lecka-Czernik, B. Partial Agonist, Telmisartan, Maintains PPARγ Serine 112 Phosphorylation, and Does Not Affect Osteoblast Differentiation and Bone Mass PLoS One 2014, 9, e96323
79. Cereto-Massagué, A.; Ojeda, M. J.; Joosten, R. P.; Valls, C.; Mulero, M.; Salvado, M. J.; Arola-Arnal, A.; Arola, L.; Garcia-Vallvé, S.; Pujadas, G. The Good, the Bad and the Dubious: VHELIBS, a Validation Helper for Ligands and Binding Sites J. Cheminf. 2013, 5, 36
80. Siersbaek, R.; Nielsen, R.; Mandrup, S. PPARgamma in Adipocyte Differentiation and Metabolism-Novel Insights from Genome-Wide Studies FEBS Lett. 2010, 584, 3242-3249