Claims
- 1. A method for the rapid determination of a ligand for a Farn soid X receptor which comprises contacting a component to be tested with an isolated Farnesoid X receptor ligand binding domain which is associated with a first marking component, and a nuclear receptor coactivator peptide associated with a second marking component, and measuring the interaction between the marking components to determine whether the component to be tested modifies binding between the Farnesoid X receptor ligand binding domain and the nuclear receptor coactivator peptide.
- 2. The method of claim 1 wherein the nuclear receptor coactivator peptide is SEQ ID NO.:1, SEQ ID NO.:2, SEQ ID NO.:3, SEQ ID NO.:4, or SEQ ID NO.:5.
- 3. The method of claim 1, wherein the interaction of the marking components is measured by comparing a signal produced by a combination of the nuclear receptor coactivator peptide, the isolated nuclear receptor binding domain and the component to be tested with a signal produced by a combination of the nuclear receptor coactivator peptide and the isolated nuclear receptor ligand binding domain in the absence of the component to be tested.
- 4. A method of identifying compounds for the treatment of diseases or disorders modulated by FXR, comprising the step of determining whether the compound interacts directly with FXR, wherein a compound that interacts directly with FXR is a compound for the treatment.
- 5. A method of claim 4 wherein said step of determining comprises the step of specifically detecting the interaction of SRC-1 (LCD2, 677-697) peptide with FXR.
- 6. A method for the rapid determination of a ligand for Farnesoid X rec ptor which comprises contacting a component to b tested with an isolat d nuclear receptor ligand binding domain which is associated with a first marking component, and a heterodimeric partner for the nuclear receptor ligand binding domain associated with a second marking component, and measuring the interaction between the marking components to determine whether the component to be tested modifies heterodimerization.
- 7. The method of claim 6 wherein the heterodimeric partner is an RXR.
- 8. A compound identified by the method of any of claims 1-7.
- 9. A compound that binds Farnesoid X receptor wherein the compound is of the following formula:
- 10. A compound of claim 9 having the following formula:
- 11. A compound of claim 9 having a detectable label.
- 12. A method for regulating l-BABP expression in a mammal which comprises activating or inhibiting the Farnasoid X Receptor.
- 13. The method of claim 12, which comprises binding an activating amount of chenodeoxycholic acid to the Farnesoid X Receptor.
- 14. The method of claim 12, which comprises inhibiting the activatation of the Farnesoid X Receptor by chenodeoxycholic acid.
- 15. A method of regulating the bile transport system in a mammal which comprises activating the Farnesoid X Receptor with a binding ligand.
- 16. The method of claim 15, wherein the binding ligand is GW4064, chenodexoycholic acid, lithocholic acid, deoxycholic acid, or a glycine or taurine conjugated conjugate derivative thereof.
- 17. The method of claim 15, wherein the Farnesoid X Receptor is activated by conjugated bile acids in tissues that express bile acid transporters.
- 18. The method of claim 17, wherein the tissue is in the terminal ileum, liver, or kidney.
- 19. The method of claim 15 for regulating intestinal cholesterol absorption, regulating bile acid flux or lowering triglycerides.
- 20. A method of treating in a mammal a disease which is affected by cholesterol, triglyceride, or bile acid levels comprising administering to a mammal in need of such treatment a therapeutically effective amount of a ligand for Farnesoid X Receptor.
- 21. A method of treating atherosclerosis, gallstone disease, lipid disorders, obesity or a cardiovascular disorder, comprising administration of a therapeutically effective amount of a compound which was identified by the method of claim 4.
- 22. The method of claim 21 wherein said compound is an activator or inhibitor of FXR heterodimers with the retinoid X receptor.
- 23. A method of blocking fatty acid absorption in intestine of a mammal in need of such blocking comprising administering to the mammal a therapeutically effective amount of a Farnesoid X receptor agonist.
- 24. The method of claim 23 for treatment of dyslipidemia, obesity or atherosclerosis.
- 25. A method of blocking protein and carbohydrate digestion in intestine of a mammal in need of such blocking comprising administering to the mammal a therapeutically effective amount of an FXR agonist.
- 26. The method of claim 25 for treatment of obesity.
- 27. A method of blocking de novo cholesterol synthesis in liver of a mammal in need of such blocking comprising administering to the mammal a therapeutically effective amount of an antagonist of FXR.
- 28. A method of blocking induction of SHP-1 expression in a mammal in need of such blocking comprising administering to the mammal a therapeutically effective amount of an antagonist of FXR.
- 29. A method of blocking SHP-1-mediated repression of CYP7A ina a mammal in need of such blocking comprising administering to the mammal a th rapeutically effective amount of an antagonist of SHP-1.
- 30. The method of any of claims 27-29 for reducing serum cholesterol levels in the mammal.
- 31. The method of any of claims 27-29 for treatment of atherosclerosis or gall stones.
- 32. The use of an RXR-specific ligand in treatment of a disease or disorder modulated by FXR.
- 33. A method of modulating a gene whose expression is regulated by FXR in a mammal comprising administering to the mammal a therapeutically effective amount of a ligand of FXR.
- 34. The method of any of claims 15, 20 or 23-33 wherein the ligand is a compound of the formula (I):
- 35. The method of any of claims 15, 20 or 23-33 wherein the ligand is the following compound (Formula (II)):
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims benefit under 35 U.S.C. 119(e) of provisional application 60/135,097.
Provisional Applications (1)
|
Number |
Date |
Country |
|
60135097 |
Dec 1998 |
US |
Continuations (1)
|
Number |
Date |
Country |
Parent |
09868397 |
Jun 2001 |
US |
Child |
10637190 |
Aug 2003 |
US |