Claims
- 1. A glucocorticoid receptor (GR) ligand having antagonist activity, but no agonist activity, in GR-mediated transactivation and no antagonist activity in GR-mediated transrepression of a glucocorticoid sensitive target gene with the proviso that said ligand is not {3,5-dibromo-4-[5-isopropyl-4-methoxy-2-(3-methyl-benzoyl-phenoxy]phenyl}-acetic acid.
- 2. A glucocorticoid receptor (GR) ligand of claim 1 which has antagonist activity, but no agonist activity, in GR-mediated transactivation and no antagonist activity in GR-mediated transrepression of a glucocorticoid sensitive target gene selected from genes having pro-inflammatory or immuno-enhancing activity, such as a gene coding for a cytokine or an adhesion molecule or an enzyme each involved in inflammation or in an immune disorder including an auto-immune disease.
- 3. A method of treating a mammalian, including a human, subject in need of glucocorticoid medication which method comprises administering to said subject as co-medication a pharmacologically active amount of a glucocorticoid receptor (GR) ligand having antagonist activity, but no agonist activity, in GR-mediated transactivation and no antagonist activity in GR-mediated transrepression of a glucocorticoid sensitive target gene.
- 4. A method according to claim 3 in which said ligand is {3,5-dibromo-4-[5-isopropyl-4-methoxy-2-(3-methyl-benzoyl-phenoxy]phenyl}-acetic acid.
- 5. A method of preventing or suppressing a side-effect associated with glucocorticoid medication of a mammalian, including a human, subject which method comprises administering to the subject as co-medication an effective amount of a glucocorticoid receptor (GR) ligand having antagonist activity, but no agonist activity, in GR-mediated transactivation and no antagonist activity in GR-mediated transrepression of a glucocorticoid sensitive target gene.
- 6. A method according to claim 5 in which said ligand is {3,5-dibromo-4-[5-isopropyl-4-methoxy-2-(3-methyl-benzoyl-phenoxy]phenyl}-acetic acid.
- 7. A pharmaceutical composition comprising a glucocorticoid receptor (GR) ligand having antagonist activity, but no agonist activity, in GR-mediated transactivation and no antagonist activity in GR-mediated transrepression of a glucocorticoid sensitive target gene and, optionally, a glucocorticoid.
- 8. A pharmaceutical composition according to claim 7 in which said ligand is {3,5-dibromo-4-[5-isopropyl-4-methoxy-2-(3-methyl-benzoyl-phenoxy]phenyl}-acetic acid.
- 9. A use of a glucocorticoid receptor (GR) ligand having antagonist activity, but no agonist activity, in GR-mediated transactivation and no antagonist activity in GR-mediated transrepression of a glucocorticoid sensitive target gene as co-medication in combination with a glucocorticoid drug in the treatment of an inflammatory disease or an immune diseases including an auto-immune diseases, in a mammalian, including a human, subject or in the treatment of a said subject in a clinical situation where treatment with a glucocorticoid is required.
- 10. A use of a glucocorticoid receptor (GR) ligand having antagonist activity, but no agonist activity, in GR-mediated transactivation and no antagonist activity in GR-mediated transrepression of a glucocorticoid sensitive target gene as co-medication in combination with a glucocorticoid drug in the treatment of a
Respiratory disease Rheumatoid disease Auto-immune disease Allergy Vascular disease Skin disease Gastrointestinal disease Renal disease Liver disease Ocular disease Ear disease Neurological disease Endocrine disease Shock Malignancy Transplantation Diabetes and obesity in a mammalian, including a human, subject.
- 11. A use according to claim 9 or 10 in which said ligand is {3,5-dibromo-4-[5-isopropyl-4-methoxy-2-(3-methyl-benzoyl-phenoxy]phenyl}-acetic acid.
- 12. A use of a glucocorticoid receptor (GR) ligand having antagonist activity, but no agonist activity, in GR-mediated transactivation and no antagonist activity in GR-mediated transrepression of a glucocorticoid sensitive target gene as co-medication in combination with a glucocorticoid drug for the preparation of a pharmaceutical composition for the treatment of an inflammatory disease or an immune disease including an auto-immune disease, in a mammalian, including a human, subject or for the treatment of a said subject in a clinical situation where treatment with a glucocorticoid is required.
- 13. A use of a glucocorticoid receptor (GR) ligand having antagonist activity, but no agonist activity, in GR-mediated transactivation and no antagonist activity in GR-mediated transrepression of a glucocorticoid sensitive target gene as co-medication in combination with a glucocorticoid drug for the preparation of a pharmaceutical composition for the treatment of a
Respiratory disease Rheumatoid disease Auto-immune disease Allergy Vascular disease Skin disease Gastrointestinal disease Renal disease Liver disease Ocular disease Ear disease Neurological disease Endocrine disease Shock Malignancy Transplantation Diabetes and obesity in a mammalian, including a human, subject.
- 14. A use according to claim 12 or 13 in which said ligand is {3,5-dibromo-4-[5-isopropyl-4-methoxy-2-(3-methyl-benzoyl-phenoxy]phenyl}-acetic acid.
- 15. A method of screening for a dissociated glucocorticoid receptor (GR) antagonist comprising:
a) contacting a candidate substance with a GR; b) determining binding of the candidate substance to the GR;, c) selecting a candidate substance having binding affinity for the GR; d) determining activity of the selected candidate substance in GR-mediated transactivation of a glucocorticoid sensitive target gene; e) selecting a candidate substance having antagonist, but no agonist transactivation activity; f) determining activity of the selected candidate substance in GR-mediated transrepression of a glucocorticoid sensitive target gene; and g) selecting the candidate substance having no antagonist transrepression activity.
- 16. A method according to claim 15 wherein the GR-mediated transactivation results in induction of tyrosine aminotransferase (TAT) in a rat hepatoma cell or in stimulation of MMTV (mouse mammary tumor virus) promoter in a HeLa cell.
- 17. A method according to claim 15 or 16 wherein the GR-mediated transrepression results in inhibition of a gene having pro-inflammatory or immuno-enhancing activity, such as a gene coding for a cytokine or an adhesion molecule or an enzyme each involved in inflammation or in a immune disorder including an auto-immune diseases.
- 18. A method according to claim 17 wherein the GR-mediated transrepression results in inhibition of TNF-α-induced activation of ICAM-1 promoter in a HeLa cell or in inhibition of LPS-induced production of IL-8 in a THP1-cell.
- 19. A method according to any one of claims 15 to 18 further comprising the step of testing the candidate substance in vivo by co-administering said substance with a glucocorticoid drug to a subject and determining the capability of the candidate substance to reduce a systemic side-effect of the glucocorticoid but retaining the anti-inflammatory activity of the glucocorticoid.
- 20. A method according to any one of claims 15 to 19 wherein said method is a high-throughput screening assay (HTS).
- 21. A method of treating a mammalian, including a human subject in the need thereof comprising the administration of a glucocorticoid receptor (GR) ligand having antagonist activity, but no agonist activity, in GR-mediated transactivation and no antagonist activity in GR-mediated transrepression of a glucocorticoid sensitive target gene as co-medication in combination with a glucocorticoid drug suffering from a condition selected from a
Respiratory disease Rheumatoid disease Auto-immune disease Allergy Vascular disease Skin disease Gastrointestinal disease Renal disease Liver disease Ocular disease Ear disease Neurological disease Endocrine disease Shock Malignancy Transplantation Diabetes and obesity.
RELATED APPLICATION
[0001] The benefit of prior United States provisional application Ser. no. 60/256,876, filed Dec. 20, 2000 is hereby claimed.
Provisional Applications (1)
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Number |
Date |
Country |
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60256876 |
Dec 2000 |
US |