Claims
- 1. A molecule that activates an RXR receptor to at least 60% of the activation of 9-cis retinoic acid, wherein the molecule comprises an RXR binding portion which binds the RXR receptor and comprises a side pocket contacting residue which has at least four contacts with the region consisting of Leu 433, Gly 429, Ile 310, Asn 306, and Trp 305 of side-pocket 1 of an RXR receptor, wherein the contacts are less than or equal to 3.5 Angstroms.
- 2. A composition comprising an RXR receptor complexed with a molecule that activates an RXR receptor to at least 60% of the activation of 9-cis retinoic acid, wherein the molecule comprises an RXR binding portion which binds the RXR receptor and comprises a side pocket contacting residue which has at least four contacts with the region consisting of Leu 433, Gly 429w, Ile 310, Asn 306, and Trp 305 of side-pocket 1 of an RXR receptor, wherein the contacts are less than or equal to 3.5 Angstroms.
- 3. A molecule that activates an RXR at least one fifth of the activity of compound 1 as measured in the adipocyte differentiation assay, wherein the molecule comprises an RXR binding portion which binds the RXR receptor and comprises a side pocket contacting residue which has at least four contacts with the region consisting of Leu 433, Gly 429, Ile 310, Asn 306, and Trp 305 of side-pocket 1 of an RXR receptor, wherein the contacts are less than or equal to 3.5 Angstroms.
- 4. The molecule of claims 1, 2, or 3, wherein the molecule does not have the structure
- 5. The molecule of claims 1, 2, or 3, wherein the molecule has at least four contacts with the region consisting of the amino acids Ile 310, Asn 306, and Trp 305 of SEQ ID NO: 1.
- 6. The molecule of claims 1, 2, or 3, wherein the molecule activates the RXR receptor at a concentration of less than or equal to 1 uM.
- 7. The molecule of claim 5, wherein the molecule activates the RXR receptor at a concentration is less than or equal to 100 nM.
- 8. The molecule of claim 1, 2, or 3, wherein the side-pocket contacting residue comprises at least three connected atoms.
- 9. The molecule of claim 1, 2, or 3, wherein there are at least 5 contacts between the atoms of the side pocket contacting residue and the region consisting of Leu 433, Gly 429, Ile 310, Asn 306, and Trp 305 of side pocket 1.
- 10. The molecule of claim 1, 2, or 3, wherein there are at least 6 contacts between the atoms of the side pocket contacting residue and the region consisting of Leu 433, Gly 429, Ile 310, Asn 306, and Trp 305 of side pocket 1.
- 11. The molecule of claim 1, 2, or 3, wherein there are at least 9 contacts between the atoms of the side pocket contacting residue and the region consisting of Leu 433, Gly 429, Ile 310, Asn 306, and Trp 305 of side pocket 1.
- 12. The molecule of claim 1, 2, or 3, wherein there are at least 14 contacts between the atoms of the side pocket contacting residue and the region consisting of Leu 433, Gly 429, Ile 310, Asn 306, and Trp 305 of side pocket 1.
- 13. The molecule of claim 1, 2, or 3, wherein there are at least 17 contacts between the atoms of the side pocket contacting residue and the region consisting of Leu 433, Gly 429, Ile 310, Asn 306, and Trp 305 of side pocket 1.
- 14. A pharmaceutical composition comprising the molecules of claim 1, 2, 3 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
- 15. The pharmaceutical composition of claim 14 that is effective to reduce blood glucose levels and lower triglyceride levels in KKAy mice.
- 16. The molecules of claim 1, 2, or 3, wherein the side pocket contacting residue comprises between 3 and 12 connected atoms.
- 17. The molecules of claim 1, 2, or 3, wherein the side pocket contacting residue comprises between 4 and 10 connected atoms.
- 18. The molecules of claim 1, 2, or 3, wherein the side pocket contacting residue comprises between 5 and 9 connected atoms.
- 19. The molecules of claim 1, 2, or 3, wherein the side pocket contacting residue comprises at least 4 connected atoms.
- 20. The molecules of claim 1, 2, or 3, wherein the side pocket contacting residue comprises at least 5 connected atoms.
- 21. The molecules of claim 1, 2, or 3, wherein the side pocket contacting residue comprises at least 6 connected atoms.
- 22. The molecules of claim 1, 2, or 3, wherein the side pocket contacting residue comprises greater than 8 connected atoms.
- 23. The composition of claims 16, wherein the connected atoms comprise carbon, hydrogen, nitrogen, phosphorus, oxygen, sulfur, fluorine, chlorine, bromine, iodine, or mixtures thereof.
- 24. The composition of claims 1, 2, or 3, wherein the side pocket contacting residue is an alkyl, a substituted alkyl, a haloalkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, a halogen, cyano, nitro, hydroxyl, acyloxy, amino, mono-substituted amino, di-substituted amino, alkylamide, alkylsulfonamide, arylsulfonamide, alkylurea, arylurea, alkylcarbamate, arylcarbamate, alkoxy, substituted alkoxy, haloalkoxy, thioalkyl, thiohaloalkyl, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide or substituted dialkylcarboxamide residue.
- 25. The composition of claims 1, 2, or 3, wherein the side pocket contacting residue is a haloalkoxy residue comprising 1 to 5 carbon atoms.
- 26. The composition of claims 1, 2, or 3, wherein the RXR binding portion comprises a substituted or unsubstituted C2-C18 cyclic organic residue.
- 27. The composition of claims 26, wherein the C2-C18 cyclic organic residue is a substituted or unsubstituted C6-C18 aromatic ring residue wherein all ring atoms are carbon, a substituted or unsubstituted C2-C18 heteroaromatic ring residue having from one to three ring atoms selected from O, S, N, NH, or a substituted or unsubstituted C2-C18 heteroaromatic ring residue having from one to three ring atoms selected from O, S, N, NH and N—R atoms or residues, wherein R comprises an alkyl, a substituted alkyl, an aryl, a substituted aryl, an acyl, a heteroaryl, or a substituted heteroaryl group.
- 28. The composition of claim 26, wherein the combination of side pocket contacting residue and the C2-C18 cyclic organic residue is a residue of Formula (II), (III), (IV) or (V):
- 29. The composition of claim 26, wherein the C2-C18 cyclic organic residue is connected to a polar binding portion comprising at least one functional group having at least one polar carbon-heteroatom or heteroatom-hydrogen bond.
- 30. The composition of claim 29, wherein the polar binding portion comprises a residue of the formula
- 31. The composition of claim 26, wherein the C2-C18 cyclic organic residue is connected to an organic binding portion comprising a C4 to C25 substituted or unsubstituted hydrocarbon residue.
- 32. The composition of claim 31, wherein the organic binding portion comprises
- 33. A method of treating a disease comprising administering a composition of claim 14 to a mammal.
- 34. A method of treating a disease comprising administering a composition of claim 14 to a human.
- 35. The method of claim 34, wherein the disease is selected from the group consisting of type 2 diabetes, hypercholesteremia, and atherosclerosis.
- 36. A method for selecting compositions that are RXR ligands which interact with a side-pocket 1 of an RXR receptor comprising 1) interacting a library of molecules with an RXR receptor, 2) removing molecules that do not interact with the RXR receptor at a predetermined level, 3) collecting the molecules that interact with side-pocket 1 of the RXR receptor.
- 37. Compounds of the formulas:
- 38. A method for selecting molecules that activate an RXR receptor having a side pocket 1 comprising:
constructing a computer representation of the 3 dimensional structure of an RXR receptor and it's side pocket 1, constructing a computer representation of the 3 dimensional structure of one or more candidate molecules, employing a computer algorithm to calculate at least some of the intermolecular interactions of the of the candidate molecule with RXR receptor and the interactions of the candidate molecule with the side pocket 1 of the RXR receptor, and selecting, based on the calculated intermolecular interactions a molecule that binds to the RXR receptor and contacts side pocket 1.
- 39. A method of selecting compounds for the treatment of type 1 diabetes, type 2 diabetes, hypercholestermia or atherosclerosis comprising designing molecules to contact side pocket 1 of an RXR receptor.
- 40. The method of claim 39, wherein the molecules are designed to have at least 4 contacts with side pocket 1 of an RXR receptor.
- 41. The method of claim 39, wherein the molecules are designed to maximize contacts with side pocket 1 of an RXR receptor.
- 42. The method of claim 39, wherein the molecules are designed to comprise between 4 and 20 contacts with side pocket 1 of an RXR receptor.
- 43. The methods of claim 40-42, wherein the molecule does not have the structure
- 44. The molecules of claims 1-3 wherein the molecule is a processed molecule.
- 45. A compound of Formula (100):
- 49. A compound of claim 45 wherein R20, R21, and R24 are alkyl or substituted alkyl; — — — — — represents a bond present; and R22 is hydroxy or an alkoxy residue having 1 to 4 carbon atoms.
I. CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. provisional application No. 60/274342, for RXR Activating Molecules, filed on Mar. 8, 2001, which is herein incorporated by reference in its entirety. U.S. Ser. No. 09/652,810, and U.S. Ser. No. 09/655,460, both filed Aug. 31, 2000, are also hereby incorporated by this reference in their entireties.
Provisional Applications (1)
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Number |
Date |
Country |
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60274342 |
Mar 2001 |
US |