Modulators of the nuclear receptor retinoic acid receptor-related orphan receptor-γ (RORγ or RORc)

Journal of Medicinal Chemistry

Volumn 57, Issue 14, 2014, Pages 5871-5892

  Fauber, Benjamin P ^a   Magnuson, Steven ^a  

^a GENENTECH INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AGENTS INTERACTING WITH TRANSMITTER, HORMONE OR DRUG RECEPTORS; GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR; INTERLEUKIN 17; INTERLEUKIN 22; N (2,2,2 TRIFLUOROETHYL) N [4 (2,2,2 TRIFLUORO 1 HYDROXY 1 TRIFLUOROMETHYLETHYL)PHENYL]BENZENESULFONAMIDE; RETINOID RELATED ORPHAN RECEPTOR GAMMA; SR 1001; SR 1078; SR 1555; SR 2211; UNCLASSIFIED DRUG;

ANIMAL CELL; BIOTECHNOLOGY; CONTROLLED STUDY; CRYSTAL STRUCTURE; GENETIC TRANSCRIPTION; LIGAND BINDING; MOUSE; NONHUMAN; OBESITY; PATENT; PROMOTER REGION; PROTEIN FUNCTION; PROTEIN STRUCTURE; REVIEW; SEQUENCE HOMOLOGY;

ANIMALS; DRUG INVERSE AGONISM; HUMANS; MODELS, MOLECULAR; MOLECULAR STRUCTURE; NUCLEAR RECEPTOR SUBFAMILY 1, GROUP F, MEMBER 3;

EID: 84903528254     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm401901d     Document Type: Review

References (139)

1. Robinson-Rechavi, M.; Garcia, H. E.; Laudet, V. The Nuclear Receptor Superfamily J. Cell Sci. 2003, 116, 585-586
2. Ottow, E.; Weinmann, H. Nuclear Receptors as Drug Targets: A Historical Perspective of Modern Drug Discovery. In Nuclear Drug Receptors as Targets, 1 st ed.; Ottow, E.; Weinmann, H., Eds.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2008; pp 1-17.
3. Via, M. C. Nuclear Receptors: The Pipeline Outlook; Insight Pharma Reports; Cambridge Healthtech Institute: Needham, MA, 2010.
4. Hirose, T.; Smith, R. J.; Jetten, A. M. RORγ: The Third Member of the ROR/RZR Orphan Receptor Subfamily that is Highly Expressed in Skeletal Muscle Biochem. Biophys. Res. Commun. 1994, 205, 1976-1983
5. Becker-André, M.; André, E.; DeLamarter, J. F. Identification of Nuclear Receptor nRNAs by RT-PCR Amplification of Conserved Zinc-Finger Motif Sequences Biochem. Biophys. Res. Commun. 1993, 194, 1371-1379
6. Carlberg, C.; Hooft van Huijsduijnen, R.; Staple, J. K.; DeLamarter, J. F.; Becker-André, M. RZRs, a New Family of Retinoid-Related Orphan Receptors that Function as both Monomers and Homodimers Mol. Endocrinol. 1994, 8, 757-770
7. Kallen, J. A.; Schlaeppi, J.-M.; Bitsch, F.; Geisse, S.; Geiser, M.; Delhon, I.; Fournier, B. X-ray Structure of the hRORα, LBD at 1.63 Å: Structural and Functional Data that Cholesterol or a Cholesterol Derivative is the Natural Ligand of RORα Structure 2002, 10, 1697-1707
8. Stehlin-Gaon, C.; Willmann, D.; Zeyer, D.; Sanglier, S.; Van Dorsselaer, A.; Renaud, J.-P.; Moras, D.; Schüle, R. All- trans Retinoic Acid is a Ligand for the Orphan Receptor RORβ Nat. Struct. Mol. Biol. 2003, 10, 820-825
9. Wang, Y.; Kumar, N.; Solt, L. A.; Richardson, T. I.; Helvering, L. M.; Crumbley, C.; Garcia-Ordonez, R. D.; Stayrook, K. R.; Zhang, X.; Novick, S.; Chalmers, M. J.; Griffin, P. R.; Burris, T. P. Modulation of Retinoic Acid Receptor-related Orphan Receptor α and γ Activity by 7-Oxygenated Sterol Ligands J. Biol. Chem. 2010, 285, 5013-5025
10. Wang, Y.; Kumar, N.; Crumbley, C.; Griffin, P. R.; Burris, T. P. A Second Class of Nuclear Receptors for Oxysterols: Regulation of RORα and RORγ Activity by 24 S -Hydroxycholesterol (Cebrosterol) Biochim. Biophys. Acta 2010, 1801, 917-923
11. Jin, L.; Martynowski, D.; Zheng, S.; Wada, T.; Xie, W.; Li, Y. Structural Basis for Hydroxycholesterols a Natural Ligands of Orphan Nuclear Receptor RORγ Mol. Endocrinol. 2010, 24, 923-929
12. Allenby, G.; Becquel, M.-T.; Saunders, M.; Kazmer, S.; Speck, J.; Rosenberger, M.; Lovey, A.; Kastner, P.; Grippo, J. F.; Chambon, P.; Levin, A. A. Retinoic Acid Receptors and Retinoid X Receptors: Interactions with Endogenous Retinoic Acids Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 30-34
13. Blumberg, B.; Evans, R. M. Orphan Nuclear Receptors-New Ligands and New Possibilities Genes Dev. 1998, 12, 3149-3155
14. Medvedev, A.; Yan, Z.-H.; Hirose, T.; Giguère, V.; Jetten, A. M. Cloning of cDNA Encoding the Murine Orphan Receptor RZR/RORγ and Characterization of its Response Element Gene 1996, 181, 199-206
15. Medvedev, A.; Chistokhina, A.; Hirose, T.; Jetten, A. M. Genomic Structure and Chromosomal Mapping of the Nuclear Orphan Receptor RORγ (RORc) Gene Genomics 1997, 46, 93-102
16. Ortiz, M. A.; Piedrafita, F. J.; Pfahl, M.; Maki, R. TOR: A New Orphan Receptor Expressed in the Thymus that can Modulate Retinoid and Thyroid Hormone Signals Mol. Endocrinol. 1995, 9, 1679-1691
17. He, Y.-W.; Deftos, M. L.; Ojala, E. W.; Bevan, M. J. RORγt, a Novel Isoform of an Orphan Receptor, Negatively Regulates Fas Ligand Expression and IL-2 Production in T Cells Immunity 1998, 9, 797-806
18. Sun, Z.; Unutmaz, D.; Zou, Y.-R.; Sunshine, M. J.; Pierani, A.; Brenner-Morton, S.; Mebius, R. E.; Littman, D. R. Requirement of RORγ in Thymocyte Survival and Lymphoid Organ Development Science 2000, 288, 2369-2373
19. Kurebayashi, S.; Ueda, E.; Sakaue, M.; Patel, D. D.; Medvedev, A.; Zhang, F.; Jetten, A. M. Retinoid-Related Orphan Receptor γ (RORγ) is Essential for Lymphoid Organogenesis and Controls Apoptosis During Thymopoiesis Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 10132-10137
20. Eberl, G.; Littman, D. R. The Role of the Nuclear Hormone Receptor RORγt in the Development of Lymph Nodes and Peyer's Patches Immunol. Rev. 2003, 195, 81-90
21. Ueda, E.; Kurebayashi, S.; Sakaue, M.; Backlund, M.; Koller, B.; Jetten, A. M. High Incidence of T-Cell Lymphomas in Mice Deficient in the Retinoid-Related Orphan Receptor RORγ Cancer Res. 2002, 62, 901-909
22. Simpson, J. G.; Gray, E. S.; Beck, J. S. Age Involution in the Normal Human Adult Thymus Clin. Exp. Immunol. 1975, 19, 261-265
23. + T Helper Cells Cell 2006, 126, 1121-1133
24. Aggarwal, S.; Ghilardi, N.; Xie, M. H.; de Sauvage, F. J.; Gurney, A. L. Interleukin-23 Promotes a Distinct CD4 T Cell Activation State Characterized by the Production of Interleukin-17 J. Biol. Chem. 2003, 278, 1910-1914
25. Tesmer, L. A.; Lundy, S. K.; Sarkar, S.; Fox, D. A. Th17 Cells in Human Disease Immunol. Rev. 2008, 223, 87-113
26. Rauen, T.; Juang, Y.-T.; Hedrich, C. M.; Kis-Toth, K.; Tsokos, G. C. A Novel Isoform of the Orphan Receptor RORγt Suppresses IL-17 Production in Human T Cells Genes Immun. 2012, 13, 346-350
27. Pappu, R.; Ramirez-Carrozzi, V.; Ota, N.; Ouyang, W.; Hu, Y. The IL-17 Family Cytokines in Immunity and Disease J. Clin. Immunol. 2010, 30, 185-195
28. Gerhardt, S.; Abbott, W. M.; Hargreaves, D.; Pauptit, R. A.; Davies, R. A.; Needham, M. R. C.; Langham, C.; Barker, W.; Aziz, A.; Snow, M. J.; Dawson, S.; Welsh, F.; Wilkinson, T.; Vaugan, T.; Beste, G.; Bishop, S.; Popovic, B.; Rees, G.; Sleeman, M.; Tuske, S. J.; Coales, S. J.; Hamuro, Y.; Russell, C. Structure of IL-17A in Complex with a Potent, Fully Human Neutralizing Antibody J. Mol. Biol. 2009, 394, 905-921
29. Hymowitz, S. G.; Filvaroff, E. H.; Yin, J.; Lee, J.; Cai, L.; Risser, P.; Maruoka, M.; Mao, W.; Foster, J.; Kelley, R. F.; Pan, G.; Gurney, A. L.; de Vos, A. M.; Starovasnik, M. A. IL-17s Adopt a Cystine Knot Fold: Structure and Activity of a Novel Cytokine, IL-17F, and Implications for Receptor Binding EMBO J. 2001, 20, 5332-5341
30. Ouyang, W.; Kolls, J. K.; Zheng, Y. The Biological Functions of T Helper 17 Cell Effector Cytokines in Inflammation Immunity 2008, 28, 454-467
31. Chabaud, M.; Durand, J. M.; Buchs, N.; Fossiez, F.; Page, G.; Frappart, L.; Miossec, P. Human Interleukin-17: A T Cell-Derived Proinflammatory Cytokine Produced by the Rheumatoid Synovium Arthritis Rheum. 1999, 42, 963-970
32. Lock, C.; Hermans, G.; Pedotti, R.; Brendolan, A.; Schadt, E.; Garren, H.; Langer-Gould, A.; Strober, S.; Cannella, B.; Allard, J.; Klonowski, P.; Austin, A.; Lad, N.; Kaminski, N.; Galli, S. J.; Oksenberg, J. R.; Raine, C. S.; Heller, R.; Steinman, L. Gene-Microarray Analysis of Multiple Sclerosis Lesions Yields New Targets Validated in Autoimmune Encephalomyelitis Nat. Med. 2002, 8, 500-508
33. Fujino, S.; Andoh, A.; Bamba, S.; Ogawa, A.; Hata, K.; Araki, Y.; Bamba, T.; Fujiyama, Y. Increased Expression of Interleukin 17 in Inflammatory Bowel Disease Gut 2003, 52, 65-70
34. Seiderer, J.; Elben, I.; Diegelmann, J.; Glas, J.; Stallhofer, J.; Tillack, C.; Pfennig, S.; Jürgens, M.; Schmechel, S.; Konrad, A.; Göke, B.; Ochsenkühn, T.; Müller-Myhsok, B.; Lohse, P.; Brand, S. Role of the Novel Th17 Cytokine IL-17F in Inflammatory Bowel Disease (IBD): Upregulated Colonic IL-17F Expression in Active Crohn's Disease and Analysis of the IL17F p.His161Arg Polymorphism in IBD Inflamm. Bowel Dis. 2008, 14, 437-445
35. Leppkes, M.; Becker, C.; Ivanov, I. I.; Hirth, S.; Wirtz, S.; Neufert, C.; Pouly, S.; Murphy, A. J.; Valezuela, D. M.; Yancopoulos, G. D.; Becher, B.; Littman, D. R.; Neurath, M. F. RORγ-Expressing Th17 Cells Induce Murine Chronic Intestinal Inflammation via Redundant Effects of IL-17A and IL-17F Gastroenterology 2009, 136, 257-267
36. Nakae, S.; Nambu, A.; Sudo, K.; Iwakura, Y. Suppresion of Immune Induction of Collagen-Induced Arthritis in IL-17-Deficient Mice J. Immunol. 2003, 171, 6173-6177
37. Lubberts, E.; Koenders, M. I.; Oppers-Walgreen, B.; van den Bersselaar, L.; Coenen-de Roo, C. J.; Joosten, L. A.; van den Bert, W. B. Treatment with a Neutralizing Anti-Murine Interleukin-17 Antibody After the Onset of Collagen-Induced Arthritis Reduces Joint Inflammation, Cartilage Destruction, and Bone Erosion Arthritis Rheum. 2004, 50, 650-659
38. Langrish, C. L.; Chen, Y.; Blumenschein, W. M.; Mattson, J.; Basham, B.; Desgwick, J. D.; McClanahan, T.; Kastelein, R. A.; Cua, D. J. IL-23 Drives a Pathogenic T Cell Population that Induces Autoimmune Inflammation J. Exp. Med. 2005, 201, 233-240
39. H17 Cells in Chronic Inflammation Nat. Rev. Drug Discovery 2012, 11, 763-776
40. Patel, D. D.; Lee, D. M.; Kolbinger, F.; Antoni, C. Effect of IL-17A Blockade with Secukinumab in Autoimmune Diseases Ann. Rheum. Dis. 2013, 72, ii116-ii123
41. Novartis Announces Secukinumab (AIN457) Demonstrated Superiority to Enbrel in Head-to-Head Phase III Psoriasis Study. http://www.novartis.com/ newsroom/media-releases/en/2013/1714715.shtml (accessed Aug 20, 2013).
42. + Innate Lymphoid Cells Immunology 2011, 132, 453-465
43. Codarri, L.; Gyülvészi, G.; Tosevski, V.; Hesske, L.; Fontana, A.; Magnenat, L.; Suter, T.; Becher, B. RORγt Drives Production of the Cytokine GM-CSF in Helper T Cells, Which is Essential for the Effector Phase of Autoimmune Neuroinflammation Nat. Immunol. 2011, 12, 560-567
44. Ma, H.-L.; Liang, S.; Li, J.; Napierata, L.; Brown, T.; Benoit, S.; Senices, M.; Gill, D.; Dunussi-Joannopoulos, K.; Collins, M.; Nickerson-Nutter, C.; Fouser, L. A.; Young, D. A. IL-22 is Required for Th-17 Cell-mediated Pathology in a Mouse Model of Psoriasis-like Skin Inflammation J. Clin. Invest. 2008, 118, 597-607
45. Rutz, S.; Eidenschenk, C.; Ouyang, W. IL-22, Not Simply a Th17 Cytokine Immunol. Rev. 2013, 252, 116
46. McQualter, J. L.; Darwiche, R.; Ewing, C.; Onuki, M.; Kay, T. W.; Hamilton, J. A.; Reid, H. H.; Bernard, C. C. A. Granulocyte Macrophage Colony-Stimulating Factor: A New Putative Therapeutic Target in Multiple Sclerosis J. Exp. Med. 2001, 194, 873-881
47. H17 Cells is Dependent on IL-1- and IL-23-Induced Production of the Cytokine GM-CSF Nat. Immunol. 2011, 12, 568-575
48. Eberl, G.; Marmon, S.; Sunshine, M.-J.; Rennert, P. D.; Choi, Y.; Littman, D. R. An Essential Function for the Nuclear Receptor RORgt in the Generation of Fetal Lymphoid Tissue Inducer Cells Nat. Immunol. 2004, 5, 64-73
49. Spits, H.; Artis, D.; Colonna, M.; Diefenbach, A.; Di Sant, J. P.; Eberl, G.; Koyasu, S.; Locksley, R. M.; McKenzie, A. N. J.; Mebius, R. E.; Powrie, F.; Vivier, E. Innate Lymphoid Cells-a Proposal for Uniform Nomenclature Nat. Immunol. 2013, 13, 145-149
50. + Natural Killer-Like Cells Nat. Immunol. 2009, 10, 66-74
51. Solt, L. A.; Kojetin, D. J.; Burris, T. P. The REV-ERBs and RORs: Molecular Links Between Circadian Rhythms and Lipid Homeostasis Future Med. Chem. 2011, 3, 623-638
52. Guillaumond, F.; Dardente, H.; Giguère, V.; Cermakian, N. Differential Control of Bmal1 Circadian Transcription by REV-ERB and ROR Nuclear Receptors J. Biol. Rhythms 2005, 20, 391-403
53. WAF1/CIP1 Expression and Hepatocyte Proliferation J. Biol. Chem. 2008, 283, 4535-4542
54. Akashi, M.; Takumi, T. The Orphan Nuclear Receptor RORα Regulates Circadian Transcription of the Mammalian Core-Clock Bmal1 Nat. Struct. Mol. Biol. 2005, 12, 441-448
55. Liu, A. C.; Tran, H. G.; Zhang, E. E.; Priest, A. A.; Welsh, D. K.; Kay, S. A. Redundant function of REV-ERBalpha and beta and non-essential role for Bmal1 cycling in transcriptional regulation of intracellular circadian rhythms PLoS Genet. 2008, 4, 1-13
56. Meissburger, B.; Ukropec, J.; Roeder, E.; Beaton, N.; Geiger, M.; Teupser, D.; Civan, B.; Langhans, W.; Nawroth, P. P.; Gasperikova, D.; Rudofsky, G.; Wolfrum, C. Adipogenesis and Insulin Sensitivity in Obesity are Regulated by Retinoid-Related Orphan Receptor Gamma EMBO Mol. Med. 2011, 3, 637-651
57. Jones, J. R.; Barrick, C.; Kim, K.-A.; Lindner, J.; Blondeau, B.; Fujimoto, Y.; Shiota, M.; Kesterson, R. A.; Kahn, B. B.; Magnuson, M. A. Deletion of PPARγ in Adipose Tissues of Mice Protects Against High Fat Diet-Induced Obesity and Insulin Resistance Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 6207-6212
58. Graham, D. J.; Ouellet-Hellstrom, R.; MaCurdy, T. E.; Ali, F.; Sholley, C.; Worrall, C.; Kelman, J. A. Risk of Acute Myocardial Infraction, Stroke, Heart Failure, and Death in Elderly Medicare Patients Treated with Rosiglitazone or Pioglitazone JAMA 2010, 304, 411-418
59. Huang, Z.; Xie, H.; Wang, R.; Sun, Z. Retinoid-Related Orphan Receptor γt is a Potential Therapeutic Target for Controlling Inflammatory Autoimmunity Expert Opin. Ther. Targets 2007, 11, 737-743
60. Huh, J. R.; Littman, D. R. Small Molecule Inhibitors of RORγt: Targeting Th17 Cells and Other Applications Eur. J. Immunol. 2012, 42, 2232-2237
61. McEwan, I. J. Nuclear Receptors: One Big Family. Methods in Molecular Biology: The Nuclear Receptor Superfamily; Walker, J. M., Ed.; Humana Press: New York, NY, 2009; Vol. 505, pp 3-18.
62. Jetten, A. M. Retinoid-Related Orphan Receptors (RORs): Critical Roles in Development, Immunity, Circadian Rhythm, and Cellular Metabolism Nucl. Recept. Signaling 2009, 7, 1-32
63. Solt, L. A.; Griffin, P. R.; Burris, T. P. Ligand Regulation of Retinoic Acid Receptor-Related Orphan Receptors: Implications for Development of Novel Therapeutics Curr. Opin. Lipidol. 2010, 21, 204-211
64. Stehlin, C.; Wurtz, J.-M.; Steinmetz, A.; Greiner, E.; Schüle, R.; Moras, D.; Renaud, J.-P. X-ray Structure of the Orphan Nuclear Receptor RORβ Ligand-Binding Domain in the Active Conformation EMBO J. 2001, 20, 5822-5831
65. Moras, D.; Gronemeyer, H. The Nuclear Receptor Ligand-Binding Domain: Structure and Function Curr. Opin. Cell Biol. 1998, 10, 384-391
66. Germain, P.; Staels, B.; Dacquet, C.; Spedding, M.; Laudet, V. Overview of Nomenclature of Nuclear Receptors Pharmcol. Rev. 2006, 58, 685-704
67. Chang, M. R.; Goswami, D.; Mercer, B. A.; Griffin, P. R. The Therapeutic Potential of RORγ Modulators in the Treatment of Human Disease J. Exp. Pharmacol. 2012, 4, 141-148
68. H17 cell Differentiation by Antagonizing RORγt Activity Nature 2011, 472, 486-490
69. Wiesenberg, I.; Missbach, M.; Kahlen, J.-P.; Schraeder, M.; Carlberg, C. Transcriptional Activation of the Nuclear Receptor RZR alpha by the Pineal Gland Hormone Melatonin and Identification of GCP 52608 as a Synthetic Ligand Nucleic Acids Res. 1995, 23, 327-333
70. Kallen, J.; Schlaeppi, J. M.; Bitsch, F.; Geisse, S.; Geiser, M.; Delhon, I.; Fournier, B. Crystal Structure of the Human RORalpha Ligand Binding Domain in Complex with Cholesterol Sulfate at 2.2 Å J. Biol. Chem. 2004, 279, 14033-14038
71. Bissantz, C.; Kuhn, B.; Stahl, M. A Medicinal Chemist's Guide to Molecular Interactions J. Med. Chem. 2010, 53, 5061-5084
72. Salonen, L. M.; Ellermann, M.; Diederich, F. Aromatic Rings in Chemical and Biological Recognition: Energetics and Structures Angew. Chem., Int. Ed. 2011, 50, 2-37
73. Fujita-Sato, S.; Ito, S.; Isobe, T.; Ohyama, T.; Wakabayashi, K.; Morishita, K.; Ando, O.; Isono, F. Structural Basis of Digoxin that Antagonizes RORγt Receptor Activity and Suppresses Th17 Cell Differentiation and Interleukin (IL)-17 Production J. Biol. Chem. 2011, 286, 31409-31417
74. Gronemeyer, H.; Gustafsson, J.-Å.; Laudet, V. Principles for Receptor Modulation of the Nuclear Receptor Superfamily Nat. Rev. Drug Discovery 2004, 3, 950-964
75. Lonard, D. M.; O'Malley, B. W. Nuclear Receptor Coregulators: Modulators of Pathology and Therapeutic Targets Nat. Rev. Endocrinol. 2012, 8, 598-604
76. Wang, Y.; Kumar, N.; Nuhant, P.; Cameron, M. D.; Istrate, M. A.; Roush, W. R.; Griffin, P. R.; Burris, T. P. Identification of SR1078, a Synthetic Agonist for the Orphan Nuclear Receptors RORα and RORγ ACS Chem. Biol. 2010, 5, 1029-1034
77. Schultz, J. R.; Tu, H.; Luk, A.; Repa, J. J.; Medina, J. C.; Li, L.; Schwendner, S.; Wang, S.; Thoolen, M.; Mangelsdorf, D. J.; Lustig, K. D.; Shan, B. Role of LXRs in Control of Lipogenesis Genes Dev. 2000, 14, 2831-2838
78. Mitro, N.; Vargas, L.; Romeo, R.; Koder, A.; Saez, E. T0901317 is a Potent PXR Ligand: Implications for the Biology Ascribed to LXR FEBS Lett. 2007, 581, 1721-1726
79. Houck, K. A.; Borchert, K. M.; Hepler, C. D.; Thomas, J. S.; Bramlett, K. S.; Michael, L. F.; Burris, T. P. T0901317 is a Dual LXR/FXR Agonist Mol. Gen. Metab. 2004, 83, 184-187
80. Zhang, W.; Zhang, J.; Fang, L.; Zhou, L.; Wang, S.; Xiang, Z.; Li, Y.; Wisely, B.; Zhang, G.; An, G.; Wang, Y.; Leung, S.; Zhong, Z. Increasing Human Th17 Differentiation Through Activation of Orphan Nuclear Receptor Retinoid Acid-related Orphan Receptor γ (RORγ) by a Class of Aryl Amide Compounds Mol. Pharmacol. 2012, 82, 583-590
81. Williams, S. C. P. Flurry of Deal-Making Surrounds New Autoimmunity Target Nat. Med. 2013, 19, 1078
82. Kumar, N.; Solt, L. A.; Conkright, J. J.; Wang, Y.; Istrate, M. A.; Busby, S. A.; Garcia-Ordonez, R. D.; Burris, T. P.; Griffin, P. R. The Benzenesulfonamide T0901317 [ N -(2,2,2-trifluoroethyl)- N -[4-[2,2,2-trifluoro- 1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide] is a Novel Retinoic Acid Receptor-related Orphan Receptor-α/γ Inverse Agonist Mol. Pharmacol. 2010, 77, 228-236
83. H17 Differentiation and Autoimmunity by a Synthetic ROR Ligand Nature 2011, 472, 491-494
84. Kumar, N.; Lyda, B.; Chang, M. R.; Lauer, J. L.; Solt, L. A.; Burris, T. P.; Kamenecka, T. M.; Griffin, P. R. Identification of SR2211: a Potent Synthetic RORγ-selective Modulator ACS Chem. Biol. 2012, 7, 672-677
85. H17 Cells and Stimulates T-regulatory Cells ACS Chem. Biol. 2012, 7, 1515-1519
86. Chang, M. R.; Lyda, B.; Kamenecka, T. M.; Griffin, P. R. Pharmacological Repression of RORγ is Therapeutic in the Collagen-induced Arthritis Experimental Model. Arthritis Rheum. [Online Early Access]. DOI: 10.1002/art.38272. Published Online: Nov 5, 2013. http://www.wiley.com (accessed Dec 21, 2013).
87. Kamenecka, T. M.; Griffin, P. R.; Shin, Y.; He, Y.; Blayo, A.-L.; Lyda, B. R.; Koenig, M.; Kumar, N.; Burris, T. Modulators of the Nuclear Hormone Receptor ROR. WO 2012/158784, Nov 22, 2012.
88. Johansson, S.; Lindholm, P.; Gullbo, J.; Larsson, R.; Bohlin, L. Cytotoxicity of Digitoxin and Related Cardiac Gylcosides in Human Tumor Cells Anti-Cancer Drugs 2001, 12, 475-483
89. Littman, D. R.; Huh, J. R.; Manel, N. G. A.; Gin, D. Y.; Krout, M. R.; Ryan, D. A. Steroid Compounds as RORγt Modulators and Uses Thereof. WO 2012/074547, Jun 7, 2012.
90. Huh, J. R.; Englund, E. E.; Wang, J.; Huang, R.; Huang, P.; Rastinejad, F.; Inglese, J.; Austin, C. P.; Johnson, R. L.; Huang, W.; Littman, D. R. Identification of Potent and Selective Diphenylpropanamide RORγ Inhibitors ACS Med. Chem. Lett. 2013, 4, 79-84
91. Khan, P. M.; El-Gendy, B. E.-D. M.; Kumar, N.; Garcia-Ordonez, R.; Lin, L.; Ruiz, C. H.; Cameron, M. D.; Griffin, P. G.; Kameneda, T. M. Small Molecule Amides as Potent RORγ Selective Modulators Bioorg. Med. Chem. Lett. 2013, 23, 532-536
92. Littman, D.; Hu, J. R.; Huang, R.; Huang, W.; Englund, E. E. Amido Compounds as RORγt Modulators and Uses Thereof. WO 2011/112263, Sep 15, 2011.
93. Deuschle, U.; Abel, U.; Kremoser, C.; Schlueter, T.; Hoffmann, T.; Perovicottstadt, S. Methods of Identification of Novel Ligands for Modulation of Orphan Nuclear Receptor RAR-Related Orphan Receptor-gamma (NR1F3) Activity. WO 2010/049144, May 6, 2010.
94. Li, Y.; Hashimoto, Y.; Agadir, A.; Kagechika, H.; Zhang, X.-K. Identification of a Novel Class of Retinoic Acid Receptor β-Selective Retinoid Antagonists and Their Inhibitor Effects on AP-1 Activity and Retinoic Acid-Induced Apoptosis in Human Breast Cancer Cells J. Biol. Chem. 1999, 274, 15360-15366
95. Bollag, W. The Development of Retinoids in Experimental and Clinical Oncology and Dermatology J. Am. Acad. Dermatol. 1983, 9, 797-805
96. Kinzel, O.; Steeneck, C.; Kleymann, G.; Albers, M.; Hoffmann, T.; Kremoser, C.; Perovicottstadt, S.; Schlüter, T. Novel Compounds for Modulation of Orphan Nuclear Receptor RAR-Related Orphan Receptor-gamma (RORγ gamma, NR1F3) Activity and for the Treatment of Chronic Inflammatory and Autoimmune Disease. WO 2011/107248, Sep 9, 2011.
97. Kinzel, O.; Gege, C.; Steeneck, C.; Kleymann, G.; Hoffmann, T. Seven-Membered Sulfonamides as Modulators of RAR-Related Orphan Receptor-gamma (RORγ, NR1F3). WO 2013/064231, May 10, 2013.
98. Steeneck, C.; Kinzel, O.; Gege, C.; Kleymann, G.; Hoffmann, T. Pyrrolo Sulfonamide Compounds for Modulation of Orphan Nuclear Receptor RAR-Related Orphan Receptor-gamma (RORgamma, NR1F3) Activity and for the Treatment of Chronic Inflammatory and Autoimmune Diseases. WO 2012/139775, Oct 18, 2012.
99. Steeneck, C.; Kinzel, O.; Gege, C.; Kleymann, G.; Hoffmann, T. Pyrrolo Carboxamides as Modulators of Orphan Nuclear Receptor RAR-Related Orphan Receptor-gamma (RORγ, NR1F3) Activity and for the Treatment of Chronic Inflammatory and Autoimmune Diseases. WO 2013/079223, Jun 6, 2013.
100. Gege, C.; Steeneck, C.; Kinzel, O.; Kleymann, G.; Hoffmann, T. Carboxamide or Sulfonamide Substituted Thiazoles and Related Derivatives as Modulators for the Orphan Nuclear Receptor RORγ. WO 2013/178362, Dec 5, 2013.
101. Glick, G. D.; Toogood, P. L.; Romero, A. G.; Vanhuis, C. A.; Aicher, T. D.; Kaub, C.; Mattson, M. N.; Thomas, W. D.; Stein, K. A.; Krogh-Jespersen, E.; Wang, Z. Tetrahydroquinoline and Related Bicyclic Compounds for Inhibition of RORγ Activity and the Treatment of Disease. WO 2012/064744, May 18, 2012.
102. Aicher, T.; Barr, K.; Lapointe, B.; Simov, V.; Stein, K.; Thomas, W.; Toogood, P.; van Huis, C.; White, C. Tetrahydronaphthyridine and Related Bicyclic Compounds for Inhibition of RORγ Activity and the Treatment of Disease. WO 2013/169704, Nov 14, 2013.
103. Aicher, T.; Barr, K.; Simov, V.; Thomas, W.; Toogood, P.; van Huis, C. Bicyclic Sulfone Compounds for Inhibition of RORγ Activity and the Treatment of Disease. WO 2013/169588, Nov 14, 2013.
104. Karstens, W. F. J.; van der Stelt, M.; Cals, J.; Azevedo, R. C. R. G.; Barr, K. J.; Zhang, H.; Beresis, R. T.; Zhang, D.; Duan, X. RORgammaT Inhibitiors. WO 2012/106995, Aug 16, 2012.
105. Japan Tobacco Inc. Clinical Development as of July 30, 2013. http://www.jt.com/investors/results/S-information/pharmaceuticals/pdf/P.L. 20130730-E.pdf (accessed Jul 31, 2013).
106. Maeba, T.; Maeda, K.; Kotoku, M.; Hirata, K.; Seki, N.; Yamanaka, H.; Sakai, T.; Hirashima, S.; Obika, S.; Shiozaki, M.; Yokota, M. Amide Compound and Pharmaceutical Application Therefor. WO 2012/147916, Nov 1, 2012.
107. Wang, Y.; Cai, W.; Liu, Q.; Xiang, J. Novel Compounds. WO 2012/027965, Mar 8, 2012.
108. Wang, Y.; Yang, T.; Liu, Q.; Xiang, J. Novel Compounds. WO 2012/028100, Mar 8, 2012.
109. Wang, Y.; Yang, T. Retinoid-Related Orphan Receptor Gamma Modulators, Composition Containing Them and Uses Thereof. WO 2012/100732, Aug 2, 2012.
110. Wang, Y.; Cai, W.; Zhang, G.; Yang, T.; Liu, Q.; Cheng, Y.; Zhou, L.; Ma, Y.; Cheng, Z.; Lu, S.; Zhao, Y.-G.; Zhang, W.; Xiang, Z.; Wang, S.; Yang, L.; Wu, Q.; Orband-Miller, L. A.; Xu, Y.; Zhang, J.; Gao, R.; Huxdorf, M.; Xiang, J.-N.; Zhong, Z.; Elliott, J. D.; Leung, S.; Lin, X. Discovery of Novel N -(5-(arylcarbonyl)thiozol-2-yl)amides and N -(5-(arylcarbonylthiophen-2-yl) amides as Potent RORγt Inhibitors Bioorg. Med. Chem. 2014, 22, 692-702
111. Wang, Y.; Yang, T. Novel Compounds. WO 2012/100734, Aug 2, 2012.
112. Wang, Y.; Cai, W.; Liu, Q.; Meng, Q.; Cheng, Y.; Yang, T.; Zhang, G.; Xiang, J.; Wu, C. Novel Compounds. WO 2013/029338, Mar 7, 2013.
113. Yang, T.; Liu, Q.; Cheng, Y.; Cai, W.; Ma, Y.; Yang, L.; Wu, Q.; Orband-Miller, L. A.; Zhou, L.; Xiang, Z.; Huxdorf, M.; Zhang, W.; Zhang, J.; Xiang, J.-N.; Leung, S.; Qiu, Y.; Zhong, Z.; Elliott, J. D.; Lin, X.; Wang, Y. Discovery of Tertiary Amide and Indole Derivatives as Potent RORγt Inverse Agonists ACS Med. Chem. Lett. 2014, 5, 65-68
114. Birault, V.; Campbell, A. J.; Harrison, S.; Le, J. Sulfonamide Compounds and Their Use in the Modulation Retinoid-related Orphan Receptor. WO 2013/045431, Apr 4, 2013.
115. Birault, V.; Campbell, A. J.; Harrison, S.; Le, J.; Shukla, L. Novel Compounds. WO 2013/160418, Oct 31, 2013.
116. Birault, V.; Campbell, A. J.; Harrison, S.; Le, J.; Shukla, L. Novel Compounds. WO 2013/160419, Oct 31, 2013.
117. Baloglu, E.; Ghosh, S.; Lobera, M.; Schmidt, D. R. Compounds and Methods. WO 2013/019621, Feb 7, 2013.
118. Baloglu, E.; Ghosh, S.; Lobera, M.; Schmidt, D. R. Compounds and Methods. WO 2013/019626, Feb 7, 2013.
119. Baloglu, E.; Ghosh, S.; Lobera, M.; Schmidt, D. R. Compounds and Methods. WO 2013/019635, Feb 7, 2013.
120. Baloglu, E.; Bohnert, G. J.; Ghosh, S.; Lobera, M.; Schmidt, D. R.; Sung, L. Compounds and Methods. WO 2013/019653, Feb 7, 2013.
121. Baloglu, E.; Bohnert, G. J.; Ghosh, S.; Lobera, M.; Schmidt, D. R.; Sung, L. Compounds and Methods. WO 2013/019682, Feb 7, 2013.
122. Baloglu, E.; Ghosh, S.; Lobera, M.; Schmidt, D. R.; Wang, Y. Therapeutic Methods. WO 2013/085890, Jun 13, 2013.
123. Wolfrum, C.; Carreira, E.; Meissburger, B. ROR Gamma Modulators. WO 2013/041519, Mar 28, 2013.
124. Yamamoto, S.; Shirai, J.; Ochida, A.; Fukase, Y.; Tomata, Y.; Sato, S.; Miura, S.; Yonemori, K.; Koyama, R. Heterocyclic Compound. WO 2013/018695, Feb 7, 2013.
125. Yamamoto, S.; Shirai, J.; Fukase, Y.; Tomata, Y.; Sato, A.; Ochida, A.; Yonemori, K.; Nakagawa, H. Condensed Heterocyclic Compound. WO 2013/042782, Mar 28, 2013.
126. Yamamoto, S.; Shirai, J.; Tomata, Y.; Kouno, M.; Ochida, A.; Sato, A.; Fukase, Y.; Yonemori, K.; Koyama, R. Heterocyclic Compound. WO 2013/100027, Jul 4, 2013.
127. Fauber, B.; René, O. Benzyl Sulfonamide Derivatives as RORc Modulators. WO 2013/092939, Jun 27, 2013.
128. Fauber, B.; René, O. Benzyl Sulfonamide Derivatives as RORc Modulators. WO 2013/092941, Jun 27, 2013.
129. Fauber, B. P.; de Leon Boenig, G.; Burton, B.; Eidenschenk, C.; Everett, C.; Gobbi, Alberto; Hymowitz, S. G.; Johnson, A.; Limatta, M.; Lockey, P.; Norman, M.; Ouyang, W.; René, O.; Wong, H. Structure-Based Design of Substituted Hexafluoroisopropanol-Arylsulfonamides as Modulators of RORc Bioorg. Med. Chem. Lett. 2013, 23, 6604-6609
130. Svensson, S.; Östberg, T.; Jacobsson, M.; Norström, C.; Stefansson, K.; Hallén, D.; Johansson, I. C.; Zachrisson, K.; Ogg, D.; Jendeberg, L. Crystal Structure of the Heterodimeric Complex of LXRα and RXRβ Ligand-binding Domains in a Fully Agonistic Conformation EMBO J. 2003, 22, 4625-4633
131. Hoerer, S.; Schmid, A.; Heckel, A.; Budzinski, R.-M.; Nar, H. Crystal Structure of the Human Liver X Receptor β Ligand-binding Domain in Complex with a Synthetic Agonist J. Mol. Biol. 2003, 334, 853-861
132. Li, L.; Liu, J.; Zhu, L.; Cutler, S.; Hasegawa, H.; Shan, B.; Medina, J. C. Discovery and Optimization of a Novel Series of Liver X Receptor-α Agonists Bioorg. Med. Chem. Lett. 2006, 16, 1638-1642
133. Gaweco, A.; Tilley, J. W.; Walker, J.; Palmer, S.; Blinn, J. ROR Modulators and Their Uses. WO 2013/159095, Oct 24, 2013.
134. Gaweco, A.; Tilley, J. W.; Walker, J.; Palmer, S.; Blinn, J. ROR Modulators and Their Uses. WO 2013/166013, Nov 7, 2013.
135. Gaweco, A.; Tilley, J. W.; Walker, J.; Palmer, S.; Blinn, J. ROR Modulators and Their Uses. WO 2013/166015, Nov 7, 2013.
136. Chaudhari, S. S.; Thomas, A.; Khairatkar-Joshi, N.; Bajpai, M. Aryl and Heteroaryl Amide Compounds as RORγt Modulator. WO 2013/171729, Nov 21, 2013.
137. Chao, J.; Enyedy, I. J.; Guertin, K.; Hutchings, R. H.; Jones, J. H.; Powell, N.; van Vloten, K. D. Biaryl-Containing Compounds as Inverse Agonists of ROR-gamma Receptors. WO 2014/008214, Jan 9, 2014.
138. Kamenecka, T. M.; Lyda, B.; Chang, M. R.; Grifin, P. R. Synthetic Modulators of the Retinoic Acid Receptor-Related Orphan Rectors Med. Chem. Commun. 2013, 4, 764-776
139. Murali Dhar, T. G.; Zhao, Q.; Markby, D. W. Targeting the Nuclear Hormone Receptor RORγt for the Treatment of Autoimmune and Inflammatory Disorders Annu. Rep. Med. Chem. 2013, 48, 169-182