Medicinal Chemistry Reviews

Volume 52, Chapter 11

ROR-gamma-T Modulators for Th17-Driven Diseases:  Progress Into the Clinic

Colin M. Tice, Yuri Bukhtiyarov, Ya-Jun Zheng, Deepak Lala, and Suresh B. Singh

1.          Introduction                                                                                                               195

            1.1        The ROR Family                                                                                             196

            1.2        Structure of RORγ and Endogenous Ligands                                              196

            1.3        Expression and Function of RORγ and RORγt                                           198

                        1.3.1     RORγt Master Regulator of TH17 and Other Immune Cells            198

                        1.3.2     RORγ Functions in Non-Immune Cells                                            199

2.         Role of RORγt in Disease                                                                                          199

            2.1        Autoimmune Diseases                                                                                  199

            2.2       Other Indications                                                                                          201

3.         Small-Molecule Modulators of RORγt                                                                     202

            3.1        Ligands of the Canonical Binding Pocket                                                  202

                        3.1.1     Hexafluoroisopropanols                                                                  202

                        3.1.2     Tertiary Sulfonamides                                                                       202

                        3.1.3     Sulfonamides of Cyclic Amines                                                        204

                        3.1.4     Biaryls                                                                                                 205

                        3.1.5     Alkylsulfonylbenzyl Compoundslls                                                 206

                        3.1.6     Piperazines                                                                                        207

                        3.1.7     Miscellaneous Compounds                                                              208

            3.2       Allosteric Ligands                                                                                          209

4.         Clinical Development of RORγt Modulators                                                          211

5.         Conclusions                                                                                                               212

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