Retinoic acid receptor antagonists as chaperone-mediated authophagy modulators and uses thereof
Compounds, compositions and methods are provided for selectively activating chaperone-mediated autophagy (CMA), protecting cells from oxidative stress, proteotoxicity and lipotoxicity, and/or antagonizing activity of retinoic acid receptor alpha (RARα) in subjects in need thereof.
1. A method of selectively activating chaperone-mediated autophagy (CMA) in a subject in need thereof comprising administering to the subject a compound of formula (II), or a combination of any compounds thereof, in an amount effective to activate CMA,
wherein the subject has Parkinson's Disease, Huntington's Disease, frontotemporal dementia, retinal degeneration, multiple sclerosis, diabetes, a lysosomal storage disorder, a retinal disease, a cardiovascular disease, myocardial infarction, cardiac hypertrophy or a cardiomyopathy, and
wherein formula (II) is
wherein
R1, R2, R3, R4, R5, R6, R8 and R9 of formula (II) are independently H, hydroxyl, halogen, SH, NO 2 , CF 3 , COOH, COOR10, CHO, CN, NH 2 , NHR10, NHCONH 2 , NHCONHR10, NHCOR10, NHSO 2 R10, OCR10, COR10, CH 2 R10, CON(R10,R11), CH═N—OR10, CH═NR10, OR10, SR10, SOR10, SO 2 R10, COOR10, CH 2 N(R10,R11), N(R10,R11), or optionally substituted lower alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalky, aryl, heteroaryl, aralkyl, or heteroaralkyl; wherein the optional substituent is one or more of F, Cl, Br, I, OH, SH, NO 2 , COOH, COOR10, R10, CHO, CN, NH 2 , NHR10, NHCONH 2 , NHCONHR10, NHCOR10, NHSO 2 R10, HOCR10, COR10, CH 2 R10, CON(R10, R11), CH═N—OR10, CH═NR10, OR10, SR10, SOR10, SO 2 R10, COOR10, CH 2 N(R10, R11), N(R10, R11);
R7 of formula (II) is H, hydroxyl, halogen, CF 3 , CN, OCF 3 , COOH, COOCH 3 , COOR10, COO(CH 2 ) 2 Si(CH 3 ) 3 , COOR10Si(CH 3 ) 3 , NHCOCH 3 , C≡C—CH 2 OH, C═C-R10-OH or optionally substituted alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cyclic or heterocyclic; wherein the optional substituent is one or more of F, Cl, Br, I, OH, SH, NO 2 , CH 3 , R10, COOH, COOR10, CHO, CN, NH 2 , NHR10, NHCONH 2 , NHCONHR10, NHCOR10, NHSO 2 R10, HOCR10, COR10, CH 2 R10, CON(R10, R11), CH═N—OR10, CH═NR10, OR10, SR10, SOR10, SO 2 R10, COOR10, CH 2 N(R10, R11), N(R10, R11);
R10 and R11 are independently H or C1-C6 alkyl; and
X is N; and Y is N or NH;
or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 , wherein the subject has reduced CMA compared to a normal subject prior to administering the compound.
3. The method of claim 1 , wherein the compound does not affect macroautophagy.
4. The method of claim 1 , wherein any one or more halogen is Br, Cl, F or I independently of any other halogen.
5. The method of claim 1 , wherein any one or more alkyl is C1-C3 alkyl independently of any other alkyl.
6. The method of claim 1 , wherein the optionally substituted aryl or heteroaryl is
where the wavy line
indicates the point of attachment of the optionally substituted aryl or heteroaryl to the main structure.
7. The method of claim 1 , wherein
Y is N,
R1 is Cl,
R2, R3, R4, R5, R6, R8 and R9 are H,
R7 is NHCOR10, and
R10 is methyl; or
a pharmaceutically acceptable salt thereof.
8. The method of claim 1 , wherein
Y is N,
R1 is Cl,
R2, R3, R4, R5, R6, R8 and R9 are H,
R7 is phenyl; or
a pharmaceutically acceptable salt thereof.
9. A method of protecting cells from oxidative stress, proteotoxicity and/or lipotoxicity in a subject in need thereof comprising administering to the subject a compound of formula (II), or a combination of any compounds thereof, in an amount effective to protect cells from oxidative stress, proteotoxicity and/or lipotoxicity,
wherein the subject has Parkinson's Disease, Huntington's Disease, frontotemporal dementia, retinal degeneration, multiple sclerosis, diabetes, a lysosomal storage disorder, a retinal disease, a cardiovascular disease, myocardial infarction, cardiac hypertrophy or a cardiomyopathy, and
wherein formula (II) is
wherein
R1, R2, R3, R4, R5, R6, R8 and R9 of formula (II) are independently H, hydroxyl, halogen, SH, NO 2 , CF 3 , COOH, COOR10, CHO, CN, NH 2 , NHR10, NHCONH 2 , NHCONHR10, NHCOR10, NHSO 2 R10, OCR10, COR10, CH 2 R10, CON(R10,R11), CH═N—OR10, CH═NR10, OR10, SR10, SOR10, SO 2 R10, COOR10, CH 2 N(R10,R11), N(R10,R11), or optionally substituted lower alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalky, aryl, heteroaryl, aralkyl, or heteroaralkyl; wherein the optional substituent is one or more of F, Cl, Br, I, OH, SH, NO 2 , COOH, COOR10, R10, CHO, CN, NH 2 , NHR10, NHCONH 2 , NHCONHR10, NHCOR10, NHSO 2 R10, HOCR10, COR10, CH 2 R10, CON(R10, R11), CH═N—OR10, CH═NR10, OR10, SR10, SOR10, SO 2 R10, COOR10, CH 2 N(R10, R11), N(R10, R11);
R7 of formula (II) is H, hydroxyl, halogen, CF 3 , CN, OCF 3 , COOH, COOCH 3 , COOR10, COO(CH 2 ) 2 Si(CH 3 ) 3 , COOR10Si(CH 3 ) 3 , NHCOCH 3 , C≡C—CH 2 OH, CC-R10-OH or optionally substituted alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cyclic or heterocyclic; wherein the optional substituent is one or more of F, Cl, Br, I, OH, SH, NO 2 , CH 3 , R10, COOH, COOR10, CHO, CN, NH 2 , NHR10, NHCONH 2 , NHCONHR10, NHCOR10, NHSO 2 R10, HOCR10, COR10, CH 2 R10, CON(R10, R11), CH═N—OR10, CH═NR10, OR10, SR10, SOR10, SO 2 R10, COOR10, CH 2 N(R10, R11), N(R10, R11);
R10 and R11 are independently H or C1-C6 alkyl; and
X is N; and Y is N or NH;
or a pharmaceutically acceptable salt thereof.
10. The method of claim 9 , wherein the cells being protected comprise cardiac cells, liver cells, neurons, myocytes, fibroblasts and/or immune cells.
11. The method of claim 9 , wherein any one or more halogen is Br, Cl, F or I independently of any other halogen.
12. The method of claim 9 , wherein any one or more alkyl is C1-C3 alkyl independently of any other alkyl.
13. The method of claim 9 , wherein any one or more aralkyl contains C1-C3 alkyl independently of any other aralkyl.
14. The method of claim 9 , wherein the compound selectively activates chaperone-mediated autophagy (CMA).
15. The method of claim 9 , wherein the compound does not affect macroautophagy.
16. The method of claim 9 , wherein the compound antagonizes activity of retinoic acid receptor alpha (RARα).
17. The method of claim 9 , wherein the optionally substituted aryl or heteroaryl is
where the wavy line
indicates the point of attachment of the optionally substituted aryl or heteroaryl to the main structure.
18. The method of claim 9 , wherein
Y is N,
R1 is Cl,
R2, R3, R4, R5, R6, R8 and R9 are H,
R7 is NHCOR10, and
R10 is methyl; or
a pharmaceutically acceptable salt thereof.
19. The method of claim 9 , wherein
Y is N,
R1 is Cl,
R2, R3, R4, R5, R6, R8 and R9 are H,
R7 is phenyl; or
a pharmaceutically acceptable salt thereof.
20. A method of antagonizing activity of retinoic acid receptor alpha (RARα) in a subject in need thereof comprising administering to the subject a compound of formula (II), or a combination of any compounds thereof, in an amount effective to act as a RARα antagonist,
wherein the subject has Parkinson's Disease, Huntington's Disease, frontotemporal dementia, retinal degeneration, multiple sclerosis, diabetes, a lysosomal storage disorder, a retinal disease, a cardiovascular disease, myocardial infarction, cardiac hypertrophy or a cardiomyopathy, and
wherein formula (II) is
wherein
R1, R2, R3, R4, R5, R6, R8 and R9 of formula (II) are independently H, hydroxyl, halogen, SH, NO 2 , CF 3 , COOH, COOR10, CHO, CN, NH 2 , NHR10, NHCONH 2 , NHCONHR10, NHCOR10, NHSO 2 R10, OCR10, COR10, CH 2 R10, CON(R10,R11), CH═N—OR10, CH═NR10, OR10, SR10, SOR10, SO 2 R10, COOR10, CH 2 N(R10,R11), N(R10,R11), or optionally substituted lower alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalky, aryl, heteroaryl, aralkyl, or heteroaralkyl; wherein the optional substituent is one or more of F, Cl, Br, I, OH, SH, NO 2 , COOH, COOR10, R10, CHO, CN, NH 2 , NHR10, NHCONH 2 , NHCONHR10, NHCOR10, NHSO 2 R10, HOCR10, COR10, CH 2 R10, CON(R10, R11), CH═N—OR10, CH═NR10, OR10, SR10, SOR10, SO 2 R10, COOR10, CH 2 N(R10, R11), N(R10, R11);
R7 of formula (II) is H, hydroxyl, halogen, CF 3 , CN, OCF 3 , COOH, COOCH 3 , COOR10, COO(CH 2 ) 2 Si(CH 3 ) 3 , COOR10Si(CH 3 ) 3 , NHCOCH 3 , C≡C—CH 2 OH, C═C-R10-OH or optionally substituted alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cyclic or heterocyclic; wherein the optional substituent is one or more of F, Cl, Br, I, OH, SH, NO 2 , CH 3 , R10, COOH, COOR10, CHO, CN, NH 2 , NHR10, NHCONH 2 , NHCONHR10, NHCOR10, NH SO 2 R10, HOCR10, COR10, CH 2 R10, CON(R10, R11), CH═N—OR10, CH═NR10, OR10, SR10, SOR10, SO 2 R10, COOR10, CH 2 N(R10, R11), N(R10, R11);
R10 and R11 are independently H or C1-C6 alkyl; and
X is N; and Y is N or NH;
or a pharmaceutically acceptable salt thereof.
21. The method of claim 20 , wherein any one or more halogen is Br, Cl, F or I independently of any other halogen.
22. The method of claim 20 , wherein any one or more alkyl is C1-C3 alkyl independently of any other alkyl.
23. The method of claim 20 , wherein the optionally substituted aryl or heteroaryl is
where the wavy line
indicates the point of attachment of the optionally substituted aryl or heteroaryl to the main structure.
24. The method of claim 20 , wherein
Y is N,
R1 is Cl,
R2, R3, R4, R5, R6, R8 and R9 are H,
R7 is NHCOR10, and
R10 is methyl; or
a pharmaceutically acceptable salt thereof.
25. The method of claim 20 , wherein
Y is N,
R1 is Cl,
R2, R3, R4, R5, R6, R8 and R9 are H,
R7 is phenyl; or
a pharmaceutically acceptable salt thereof.