Modulators of retinoid-related orphan receptor gamma

Abstract

Methods for modulating (inhibiting or stimulating) retinoid-related orphan receptor γ (RORγ) activity. This modulation has numerous effects, including inhibition of T H -17 cell function and/or T H -17 cell activity, and inhibition of re-stimulation of T H -17 cells, which are beneficial to treatment of inflammation and autoimmune disorders. Stimulation of RORγ results in stimulation of T H -17 cell function and/or activity which is beneficial for immune-enhancing compositions (e.g., vaccines).

What is claimed is: 
     
         1 . A method of inhibiting T H -17 cell differentiation, function or activity in an individual afflicted with multiple sclerosis, psoriasis, Crohn's disease, asthma, rheumatoid arthritis, uveitis or psoriatic arthritis, comprising administering to said individual an effective amount of a small organic molecule antagonist of RORγ, wherein said small organic molecule antagonist has a molecular weight of less than about 600 daltons, wherein the ability of said small organic molecule to act as a RORγ antagonist is demonstrable by its ability to inhibit transcription through the RORγ ligand binding domain and to regulate the affinity of the RORγ ligand binding domain with a coregulatory peptide at concentrations of 1 μM or less. 
     
     
         2 . The method of  claim 1 , wherein said T H -17 cell function or activity is release of a cytokine. 
     
     
         3 . The method of  claim 2 , wherein said cytokine is interleukin-17 or interleukin-22. 
     
     
         4 . The method of  claim 1 , wherein the RORγ antagonist is orally administered. 
     
     
         5 . The method of  claim 1  wherein the RORγ antagonist is locally administered. 
     
     
         6 . The method of  claim 1  wherein said effective amount of a RORγ antagonist is administered on a daily basis without resulting in weight loss or hypertriglyceridemia. 
     
     
         7 . The method of  claim 1 , wherein the coregulatory peptide binding is measured by a method selected from the group consisting of fluorescence resonance energy transfer (FRET), fluorescence polarization, time-resolved FRET (TR-FRET) and Alpha Screen. 
     
     
         8 . A method of treating multiple sclerosis, psoriasis, Crohn's disease, asthma, rheumatoid arthritis, uveitis or psoriatic arthritis, in an individual, comprising identifying an individual in need of such treatment, and administering to said individual an effective amount of a selective small organic molecule antagonist of RORγ, wherein said small organic molecule antagonist has a molecular weight of less than about 600 daltons, wherein the ability of small organic molecule to act as a RORγ antagonist is demonstrable by its ability to inhibit transcription through the RORγ ligand binding domain and to regulate the affinity of the RORγ ligand binding domain with a coregulatory peptide at concentrations of 1 μM or less. 
     
     
         9 . The method of  claim 8 , wherein the RORγ antagonist is orally administered. 
     
     
         10 . The method of  claim 8 , wherein said RORγ antagonist is locally administered. 
     
     
         11 . The method of  claim 8 , wherein said effective amount of RORγ antagonist is administered on a daily basis without resulting in weight loss or hypertriglyceridemia. 
     
     
         12 . The method of  claim 8 , wherein the coregulatory peptide is measured by a method selected from the group consisting of fluorescence resonance energy transfer (FRET), fluorescence polarization, time-resolved FRET (TR-FRET) and Alpha Screen.