NITROXIDES FOR USE IN TREATING OR PREVENTING HYPERCHOLESTEROLEMIA

1 . A method for altering intracellular levels of one or more proteins associated with hypercholesterolemia, comprising:

identifying an individual in need of altering levels of hypercholesterolemia-associated proteins; and

administering to that individual an effective amount of a nitroxide antioxidant.

2 . The method of claim 1 wherein the nitroxide antioxidant is selected from the group consisting of

or a pharmaceutically acceptable salt thereof

wherein X is selected from O. and OH, and R is selected from COOH, CONH, CN, and CH 2 NH 2 ;

or a pharmaceutically acceptable salt thereof

wherein X is selected from O. and OH, and R 1 is selected from CH 3 and spirocylohexyl, and R 2 is selected from C 2 H 5 and spirocyclohexyl;

or a pharmaceutically acceptable salt thereof

wherein X is selected from O. and OH and R is CONH;

or a pharmaceutically acceptable salt thereof

wherein X is selected from O. and OH and R is H, OH, and NH 2 ;

wherein R 1 is —CH 3 ; R 2 is —C 2 H 5 , —C 3 H 7 , —C 4 H 9 , —C 5 H 11 , —C 6 H 13 , —CH 2 —CH(CH 3 ) 2 , —CHCH 3 C 2 H 5 , or —(CH 2 ) 7 —CH 3 , or wherein R 1 and R 2 together form spirocyclopentane, spirocyclohexane, spirocycloheptane, spirocyclooctane, 5-cholestane, or norbornane; R 3 is —O. or —OH, or a physiologically acceptable salt thereof which has antioxidant activity;

wherein R 3 is —O. or —OH; and

wherein R 4 and R 5 combine together with the nitrogen to form a heterocyclic group; wherein the atoms in the heterocyclic group (other than the N atom shown in the formula) may be all C atoms or may be C atoms and one or more N, O and/or S atoms; or

wherein R 4 and R 5 combine together to form substituted or unsubstituted pyrrole, imidazole, oxazole, thiazole, pyrazole, 3-pyrroline, pyrrolidine, pyridine, pyrimidine, or purine; or

wherein R 4 and R 5 themselves comprise a substituted or unsubstituted cyclic or heterocyclic group;

2-ethyl-2,5,5-trimethyl-3-oxazolidine-1-oxyl, 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL), 4-amino-2,2,6,6-tetramethyl-1-piperidinyloxy (Tempamine), 3-Aminomethyl-PROXYL, 3-Cyano-PROXYL, 3-Carbamoyl-PROXYL, 3-Carboxy-PROXYL, 4-oxo-TEMPO, 4-amino-TEMPO, 4-(2-bromoacetamido)-TEMPO, 4-(ethoxyfluorophosphonyloxy-TEMPO, 4-hydroxy-TEMPO, 4-(2-iodoacetamido)-TEMPO, 4-isothiocyanato-TEMPO, 4-maleimido-TEMPO, 4-(4-nitrobenzoyloxyl)-TEMPO, and 4-phosphonooxy-TEMPO.

3 . The method of claim 1 , wherein the nitroxide antioxidant is 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl.

4 . The method of claim 1 , wherein the level of the hypercholesterolemia associated protein is decreased.

5 . The method of claim 4 , wherein the hypercholesterolemia associated protein is LSS, FDPS, or NSDHL.

6 . The method of claim 1 , wherein the effective amount of a nitroxide antioxidant is within a range of 0.01-300 mg/kg.

7 . The method of claim 1 , wherein the effective amount of a nitroxide antioxidant is within a range of 0.1-250 mg/kg.

8 . The method of claim 1 , wherein the effective amount of a nitroxide antioxidant is within a range of 1-200 mg/kg.

9 . The method of claim 1 , wherein the effective amount of a nitroxide antioxidant is within a range of 2-150 mg/kg.

10 . The method of claim 1 , wherein the effective amount of a nitroxide antioxidant is within a range of 5-125 mg/kg.

11 . The method of claim 1 , wherein the effective amount of a nitroxide antioxidant is within a range of 7-100 mg/kg.

12 . The method of claim 1 , wherein the effective amount of a nitroxide antioxidant is within a range of 10-75 mg/kg.

13 . The method of claim 1 , wherein the effective amount of a nitroxide antioxidant is within a range of 15-30 mg/kg.

14 . A method for inhibiting the progression of hypercholesterolemia associated with a protein, comprising:

identifying an individual affected by or at risk for the protein-associated hypercholesterolemia; and

administering to that individual an amount of a nitroxide antioxidant effective to alter expression of a gene associated with the protein-associated hypercholesterolemia.

15 . The method of claim 14 wherein the nitroxide is selected from the group consisting of

or a pharmaceutically acceptable salt thereof

wherein X is selected from O. and OH, and R is selected from COOH, CONH, CN, and CH 2 NH 2 ;

or a pharmaceutically acceptable salt thereof

wherein X is selected from O. and OH, and R 1 is selected from CH 3 and spirocylohexyl, and R 2 is selected from C 2 H 5 and spirocyclohexyl;

or a pharmaceutically acceptable salt thereof

wherein X is selected from O. and OH and R is CONH;

or a pharmaceutically acceptable salt thereof

wherein X is selected from O. and OH and R is H, OH, and NH 2 ;

wherein R 1 is —CH 3 ; R 2 is —C 2 H 5 , —C 3 H 7 , —C 4 H 9 , —C 5 H 11 , —C 6 H 13 , —CH 2 CH(CH 3 ) 2 , —CHCH 3 C 2 H 5 , or —(CH 2 ) 7 —CH 3 , or wherein R 1 and R 2 together form spirocyclopentane, spirocyclohexane, spirocycloheptane, spirocyclooctane, 5-cholestane, or norbornane; R 3 is —O. or —OH, or a physiologically acceptable salt thereof which has antioxidant activity;

wherein R 3 is —O. or —OH; and

wherein R 4 and R 5 combine together with the nitrogen to form a heterocyclic group; wherein the atoms in the heterocyclic group (other than the N atom shown in the formula) may be all C atoms or may be C atoms and one or more N, O and/or S atoms; or

wherein R 4 and R 5 combine together to form substituted or unsubstituted pyrrole, imidazole, oxazole, thiazole, pyrazole, 3-pyrroline, pyrrolidine, pyridine, pyrimidine, or purine; or

wherein R 4 and R 5 themselves comprise a substituted or unsubstituted cyclic or heterocyclic group;

2-ethyl-2,5,5-trimethyl-3-oxazolidine-1-oxyl, 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL), 4-amino-2,2,6,6-tetramethyl-1-piperidinyloxy (Tempamine), 3-Aminomethyl-PROXYL, 3-Cyano-PROXYL, 3-Carbamoyl-PROXYL, 3-Carboxy-PROXYL, 4-oxo-TEMPO, 4-amino-TEMPO, 4-(2-bromoacetamido) -TEMPO, 4-(ethoxyfluorophosphonyloxy)-TEMPO, 4-hydroxy-TEMPO, 4-(2-iodoacetamido)-TEMPO, 4-isothiocyanato-TEMPO, 4-maleimido-TEMPO, 4-(4-nitrobenzoyloxyl) -TEMPO, and 4-phosphonooxy-TEMPO.

16 . The method of claim 14 , where the expression of the gene is decreased.

17 . The method of claim 15 , wherein the gene is LSS, FDPS, or NSDHL.

18 . The method of claim 16 wherein the nitroxide antioxidant is 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl.

19 . The method of claim 14 , wherein the effective amount of a nitroxide antioxidant is within a range of 0.01-300 mg/kg.

20 . The method of claim 15 , wherein the effective amount of a nitroxide antioxidant is within a range of 0.1-250 mg/kg.

21 . The method of claim 14 , wherein the effective amount of a nitroxide antioxidant is within a range of 1-200 mg/kg.

22 . The method of claim 14 , wherein the effective amount of a nitroxide antioxidant is within a range of 2-150 mg/kg.

23 . The method of claim 14 , wherein the effective amount of a nitroxide antioxidant is within a range of 5-125 mg/kg.

24 . The method of claim 14 , wherein the effective amount of a nitroxide antioxidant is within a range of 7-100 mg/kg.

25 . The method of claim 14 , wherein the effective amount of a nitroxide antioxidant is within a range of 10-75 mg/kg.

26 . The method of claim 14 , wherein the effective amount of a nitroxide antioxidant is within a range of 15-30 mg/kg.

27 . A method for treating hypercholesterolemia, comprising:

administering to a patient with hypercholesterolemia an amount of a nitroxide antioxidant effective to reduce fasting plasma total cholesterol.

28 . The method of claim 27 wherein the nitroxide is selected from the group consisting of

or a pharmaceutically acceptable salt thereof

wherein X is selected from O. and OH, and R is selected from COOH, CONH, CN, and CH 2 NH 2 ;

or a pharmaceutically acceptable salt thereof

wherein X is selected from O. and OH, and R 1 is selected from CH 3 and spirocylohexyl, and R 2 is selected from C 2 H 5 and spirocyclohexyl;

or a pharmaceutically acceptable salt thereof

wherein X is selected from O. and OH and R is CONH;

or a pharmaceutically acceptable salt thereof

wherein X is selected from O. and OH and R is H, OH, and NH 2 ;

wherein R 1 is —CH 3 ; R 2 is —C 2 H 5 , —C 3 H 7 , —C 4 H 9 , —C 5 H 11 , —C 6 H 13 , —CH 2 —CH(CH 3 ) 2 , —CHCH 3 C 2 H 5 , or —(CH 2 ) 7 —CH 3 , or wherein R 1 and R 2 together form spirocyclopentane, spirocyclohexane, spirocycloheptane, spirocyclooctane, 5-cholestane, or norbornane; R 3 is —O. or —OH, or a physiologically acceptable salt thereof which has antioxidant activity;

wherein R 3 is —O. or —OH; and

wherein R 4 and R 5 combine together with the nitrogen to form a heterocyclic group; wherein the atoms in the heterocyclic group (other than the N atom shown in the formula) may be all C atoms or may be C atoms and one or more N, O and/or S atoms; or

wherein R 4 and R 5 combine together to form substituted or unsubstituted pyrrole, imidazole, oxazole, thiazole, pyrazole, 3-pyrroline, pyrrolidine, pyridine, pyrimidine, or purine; or

wherein R 4 and R 5 themselves comprise a substituted or unsubstituted cyclic or heterocyclic group;

2-ethyl-2,5,5-trimethyl-3-oxazolidine-1-oxyl, 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL), 4-amino-2,2,6,6-tetramethyl-1-piperidinyloxy (Tempamine), 3-Aminomethyl-PROXYL, 3-Cyano-PROXYL, 3-Carbamoyl-PROXYL, 3-Carboxy-PROXYL, 4-oxo-TEMPO, 4-amino-TEMPO, 4-(2-bromoacetamido)-TEMPO, 4-(ethoxyfluorophosphonyloxy)-TEMPO, 4-hydroxy-TEMPO, 4-(2-iodoacetamido)-TEMPO, 4-isothiocyanato-TEMPO, 4-maleimido-TEMPO, 4-(4-nitrobenzoyloxyl)-TEMPO, and 4-phosphonooxy-TEMPO.

29 . The method of claim 27 , wherein the effective amount of a nitroxide antioxidant is within a range of 0.01-300 mg/kg.

30 . The method of claim 27 , wherein the effective amount of a nitroxide antioxidant is within a range of 0.1-250 mg/kg.

31 . The method of claim 27 , wherein the effective amount of a nitroxide antioxidant is within a range of 1-200 mg/kg.

32 . The method of claim 27 , wherein the effective amount of a nitroxide antioxidant is within a range of 10-75 mg/kg.

33 . The method of claim 27 , wherein the effective amount of a nitroxide antioxidant is within a range of 15-30 mg/kg.

34 - 37 . (canceled)

38 . A method to return HDL levels to normal ranges comprising

identifying an individual with abnormal HDL levels; and

administering to that individual and effective amount of a nitroxide antioxidant.

39 . The method of claim 38 wherein the nitroxide antioxidant is 4-hydroxy-2,2,6,6-tetramethyl-1-piperidinyloxyl.