RXR activating molecules

Abstract

Disclosed are molecules that activate an RXR receptor, wherein the molecule comprises an RXR binding portion which binds the RXR receptor and comprises a side pocket contacting residue which contacts a side-pocket 1 of an RXR receptor.

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, and wherein the molecule does not have the structure:  
       
         
           
           
               
               
           
         
       
       wherein: 
 n and m are independently 0 or 1;  
 R 1  and R 2  are 1) independently or together hydrogen, alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, hydroxyl, acyl, amino, mono-substituted amino, di-substituted amino, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide or haloalkoxy; or 2) R 1  and R 2  together with the aromatic ring bonded thereto form a cycloalkyl, substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl residue that may optionally comprise 1 or 2 heteroatoms selected from O, S, NH or N-alkyl;  
 R 3  and R 4  are independently or together hydrogen, alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogen, cyano, nitro, hydroxyl, acyloxy, amino, mono-substituted amino, di-substituted amino, alkylsulfonamide, arylsulfonamide, alkylurea, arylurea, alkylcarbamate, arylcarbamate, heteroaryl, alkoxy, substituted alkoxy, haloalkoxy, thioalkyl, thiohaloalkyl, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide or substituted dialkylcarboxamide;  
 A is —CR 6 R 7 — where R6 and R7 are independently or together hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy or haloalkoxy; or R 6  and R 7  together form a cycloalkyl residue that may optionally comprise 1 or 2 heteroatoms selected from O, S, NH and N-alkyl;  
 Ar is Formula (II), (III), (IV) or (V):  
                     
 wherein R 8 , R 9  and R 10  are independently or together hydrogen, alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, 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;  
 R 5  is hydrogen, halogen, hydroxy, alkyl or substituted alkyl;  
                     
 represents a bond present or absent; and  
 W, X, Y and Z are independently or together —C(O)—, —C(S)—, —S—, —O— or —NH— residues that together form a 2,4-thiazolidinedione, 2-thioxo-4-thiazolidinedione, isoxazolidinedione, 2,4-imidazolidinedione or 2-thioxo-4-imidazolidinedione residue;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         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 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, wherein the molecule does not have the structure  
       
         
           
           
               
               
           
         
       
       wherein: 
 n and m are independently 0 or 1;  
 R 1  and R 2  are 1) independently or together hydrogen, alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, hydroxyl, acyl, amino, mono-substituted amino, di-substituted amino, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide or haloalkoxy; or 2) R 1  and R 2  together with the aromatic ring bonded thereto form a cycloalkyl, substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl residue that may optionally comprise 1 or 2 heteroatoms selected from O, S, NH or N-alkyl;  
 R 3  and R 4  are independently or together hydrogen, alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogen, cyano, nitro, hydroxyl, acyloxy, amino, mono-substituted amino, di-substituted amino, alkylsulfonamide, arylsulfonamide, alkylurea, arylurea, alkylcarbamate, arylcarbamate, heteroaryl, alkoxy, substituted alkoxy, haloalkoxy, thioalkyl, thiohaloalkyl, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide or substituted dialkylcarboxamide;  
 A is —CR 6 R 7 — where R6 and R7 are independently or together hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy or haloalkoxy; or R 6  and R 7  together form a cycloalkyl residue that may optionally comprise 1 or 2 heteroatoms selected from O, S, NH and N-alkyl;  
 Ar is Formula (II), (III), (IV) or (V):  
                     
 wherein R 8 , R 9  and R 10  are independently or together hydrogen, alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, 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;  
 R 5  is hydrogen, halogen, hydroxy, alkyl or substituted alkyl;  
                     
 represents a bond present or absent; and  
 W, X, Y and Z are independently or together —C(O)—, —C(S)—, —S—, —O— or —NH— residues that together form a 2,4-thiazolidinedione, 2-thioxo-4-thiazolidinedione, isoxazolidinedione, 2,4-imidazolidinedione or 2-thioxo-4-imidazolidinedione residue;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         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, wherein the molecule does not have the structure:                          wherein:    n and m are independently 0 or 1;    R 1  and R 2  are 1) independently or together hydrogen, alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, hydroxyl, acyl, amino, mono-substituted amino, di-substituted amino, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide or haloalkoxy; or 2) R 1  and R 2  together with the aromatic ring bonded thereto form a cycloalkyl, substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl residue that may optionally comprise 1 or 2 heteroatoms selected from O, S, NH or N-alkyl;    R 3  and R4 are independently or together hydrogen, alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogen, cyano, nitro, hydroxyl, acyloxy, amino, mono-substituted amino, di-substituted amino, alkylsulfonamide, arylsulfonamide, alkylurea, arylurea, alkylcarbamate, arylcarbamate, heteroaryl, alkoxy, substituted alkoxy, haloalkoxy, thioalkyl, thiohaloalkyl, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide or substituted dialkylcarboxamide;    A is —CR 6 R 7 — where R6 and R7 are independently or together hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy or haloalkoxy; or R 6  and R 7  together form a cycloalkyl residue that may optionally comprise 1 or 2 heteroatoms selected from O, S, NH and N-alkyl;    Ar is Formula (II), (III), (IV) or (V):                          wherein R 8 , R 9  and R 10  are independently or together hydrogen, alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, 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;    R 5  is hydrogen, halogen, hydroxy, alkyl or substituted alkyl;                          represents a bond present or absent; and    W, X, Y and Z are independently or together —C(O)—, —C(S)—, —S—, —O— or —NH— residues that together form a 2,4-thiazolidinedione, 2-thioxo-4-thiazolidinedione, isoxazolidinedione, 2,4-imidazolidinedione or 2-thioxo-4-imidazolidinedione residue;    or a pharmaceutically acceptable salt thereof.    
     
     
         4 . 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.  
     
     
         5 . 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.  
     
     
         6 . The molecule of  claim 4 , wherein the molecule activates the RXR receptor at a concentration is less than or equal to 100 nM.  
     
     
         7 . The molecule of  claim 1 ,  2 , or  3 , wherein the side-pocket contacting residue comprises at least three connected atoms.  
     
     
         8 . 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.  
     
     
         9 . A pharmaceutical composition comprising the molecules of  claim 1 ,  2 ,  3  or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.  
     
     
         10 . The pharmaceutical composition of  claim 9  that is effective to reduce blood glucose levels and lower triglyceride levels in KKA y  mice.  
     
     
         11 . The molecules of  claim 1 ,  2 , or  3 , wherein the side pocket contacting residue comprises between 3 and 12 connected atoms.  
     
     
         12 . The molecules of  claim 1 ,  2 , or  3 , wherein the side pocket contacting residue comprises greater than 8 connected atoms.  
     
     
         13 . The composition of claims  11 , wherein the connected atoms comprise carbon, hydrogen, nitrogen, phosphorus, oxygen, sulfur, fluorine, chlorine, bromine, iodine, or mixtures thereof.  
     
     
         14 . 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.  
     
     
         15 . The composition of claims  1 ,  2 , or  3 , wherein the side pocket contacting residue is a haloalkoxy residue comprising 1 to 5 carbon atoms.  
     
     
         16 . The composition of claims  1 ,  2 , or  3 , wherein the RXR binding portion comprises a substituted or unsubstituted C 2 -C 18  cyclic organic residue.  
     
     
         17 . The composition of claims  16 , wherein the C 2 -C 18  cyclic organic residue is a substituted or unsubstituted C 6 -C 18  aromatic ring residue wherein all ring atoms are carbon, a substituted or unsubstituted C 2 -C 18  heteroaromatic ring residue having from one to three ring atoms selected from O, S, N, NH, or a substituted or unsubstituted C 2 -C 18  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.  
     
     
         18 . The composition of  claim 16 , wherein the combination of side pocket contacting residue and the C 2 -C 18  cyclic organic residue is a residue of Formula (II), (III), (IV) or (V):  
       
         
           
           
               
               
           
         
       
       wherein R 8 , R 9  and R 10  are independently or together hydrogen, alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, 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.  
     
     
         19 . The composition of  claim 16 , wherein the C 2 -C 18  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.  
     
     
         20 . The composition of  claim 19 , wherein the polar binding portion comprises a residue of the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 m is an integer 0 or 1;  
 R 5  is hydrogen, halogen, hydroxy, alkyl or substituted alkyl;  
                     
 represents a bond present or absent;  
 W, X, Y and Z are independently or together —C(O)—, —C(S)—, —S—, —O— or —NH— residues that together form a 2,4-thiazolidinedione, 2-thioxo-4-thiazolidinedione, isoxazolidinedione, 2,4-imidazolidinedione or 2-thioxo-4-imidazolidinedione residue.  
 
     
     
         21 . The composition of  claim 16 , wherein the C 2 -C 18  cyclic organic residue is connected to an organic binding portion comprising a C 4  to C 25  substituted or unsubstituted hydrocarbon residue.  
     
     
         22 . The composition of  claim 21 , wherein the organic binding portion comprises  
       
         
           
           
               
               
           
         
       
       wherein: 
 n and m are independently 0 or 1;  
 R 1  and R 2  are 1) independently or together hydrogen, alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, hydroxyl, acyl, amino, mono-substituted amino, di-substituted amino, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide or haloalkoxy; or 2) R1 and R2 together with the aromatic ring bonded thereto form a cycloalkyl, substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl residue that may optionally comprise 1 or 2 heteroatoms selected from O, S, NH or N-alkyl;  
 R 3  and R 4  are independently or together hydrogen, alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogen, cyano, nitro, hydroxyl, acyloxy, amino, mono-substituted amino, di-substituted amino, alkylsulfonamide, arylsulfonamide, alkylurea, arylurea, alkylcarbamate, arylcarbamate, heteroaryl, alkoxy, substituted alkoxy, haloalkoxy, thioalkyl, thiohaloalkyl, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide or substituted dialkylcarboxamide; and  
 A is —CR 6 R 7 — where R 6  and R 7  are independently or together hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy or haloalkoxy; or R 6  and R 7  together form a cycloalkyl residue that may optionally comprise 1 or 2 heteroatoms selected from O, S, NH and N-alkyl.  
 
     
     
         23 . A method of treating a disease comprising administering a composition of  claim 9  to a mammal.  
     
     
         24 . A method of treating a disease comprising administering a composition of  claim 9  to a human.  
     
     
         25 . The method of  claim 24 , wherein the disease is selected from the group consisting of type 2 diabetes, hypercholesteremia, and atherosclerosis.  
     
     
         26 . 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.  
     
     
         27 . A compounds of the formula:  
       
         
           
           
               
               
           
         
       
     
     
         28 . 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.    
     
     
         29 . 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.  
     
     
         30 . The method of  claim 29 , wherein the molecules are designed to have at least 4 contacts with side pocket 1 of an RXR receptor.  
     
     
         31 . The method of  claim 29 , wherein the molecules are designed to maximize contacts with side pocket 1 of an RXR receptor.  
     
     
         32 . The method of  claim 29 , wherein the molecules are designed to comprise between 4 and 20 contacts with side pocket 1 of an RXR receptor.  
     
     
         33 . The methods of claim  30 - 32 , wherein the molecule does not have the structure  
       
         
           
           
               
               
           
         
       
       wherein: 
 n and m are independently 0 or 1;  
 R 1  and R 2  are 1) independently or together hydrogen, alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, hydroxyl, acyl, amino, mono-substituted amino, di-substituted amino, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide or haloalkoxy; or 2) R 1  and R 2  together with the aromatic ring bonded thereto form a cycloalkyl, substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl residue that may optionally comprise 1 or 2 heteroatoms selected from O, S, NH or N-alkyl;  
 R 3  and R 4  are independently or together hydrogen, alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogen, cyano, nitro, hydroxyl, acyloxy, amino, mono-substituted amino, di-substituted amino, alkylsulfonamide, arylsulfonamide, alkylurea, arylurea, alkylcarbamate, arylcarbamate, heteroaryl, alkoxy, substituted alkoxy, haloalkoxy, thioalkyl, thiohaloalkyl, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide or substituted dialkylcarboxamide;  
 A is —CR 6 R 7 — where R6 and R7 are independently or together hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy or haloalkoxy; or R 6  and R 7  together form a cycloalkyl residue that may optionally comprise 1 or 2 heteroatoms selected from O, S, NH and N-alkyl;  
 Ar is Formula (II), (III), (IV) or (V):  
                     
 wherein R 8 , R 9  and R 10  are independently or together hydrogen, alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, 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;  
 R 5  is hydrogen, halogen, hydroxy, alkyl or substituted alkyl;  
                     
 represents a bond present or absent; and  
 W, X, Y and Z are independently or together —C(O)—, —C(S)—, —S—, —O— or —NH— residues that together form a 2,4-thiazolidinedione, 2-thioxo-4-thiazolidinedione, isoxazolidinedione, 2,4-imidazolidinedione or 2-thioxo-4-imidazolidinedione residue;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         34 . The molecules of claims  1 - 3  wherein the molecule is a processed molecule.