Retinoic acid receptor antagonists as chaperone-mediated autophagy 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 compound having the structure
wherein
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , and R 9 are independently H, hydroxyl, halogen, SH, NO 2 , CF 3 , COOH, COOR 10 , CHO, CN, NH 2 , NHR 10 , NHCONH 2 , NHCONHR 10 , NHCOR 10 , NHSO 2 R 10 , OCR 10 , COR 10 , CH 2 R 10 , CON(R 10 ,R 11 ), CH═N—OR 10 , CH═NR 10 , OR 10 , SR 10 , SOR 10 , SO 2 R 10 , COOR 10 , CH 2 N(R 10 ,R 11 ), N(R 10 ,R 11 ), 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, COOR 10 , R 10 , CHO, CN, NH 2 , NHR 10 , NHCONH 2 , NHCONHR 10 , NHCOR 10 , NHSO 2 R 10 , HOCR 10 , COR 10 , CH 2 R 10 , CON(R 10 , R 11 ), CH═N—OR 10 , CH═NR 10 , OR 10 , SR 10 , SOR 10 , SO 2 R 10 , COOR 10 , CH 2 N(R 10 , R 11 ), N(R 10 , R 11 ;
R 7 is CF 3 , CN, OCF 3 , COOH, COOCH 3 , COOR 10 , COO(CH 2 ) 2 Si(CH 3 ) 3 , COOR 10 Si(CH 3 ) 3 , NHCOCH 3 , C═C—CH 2 OH, C═C—R 10 —OH, substituted alkyl, or optionally substituted aryl, heteroaryl, aralkyl, heteroaroaralkyl, cyclic or heterocyclic;
wherein the optional substituent is one or more of F, Cl, Br, I, OH, SH, NO 2 , CH 3 , R 10 , COOH, COOR 10 , CHO, CN, NH 2 , NHR 10 , NHCONH 2 , NHCONHR 10 , NHCOR 10 , NHSO 2 R 10 , HOCR 10 , COR 10 , CH 2 R 10 , CON(R 10 , R 11 ), CH═N—OR 10 , CH═NR 10 , OR 10 , SR 10 , SOR 10 , SO 2 R 10 , COOR 10 , CH 2 N(R 10 , R 11 ), N(R 10 , R 11 ); and
R 10 and R 11 are independently H or C 1 -C 6 alkyl;
or a pharmaceutically acceptable salt thereof,
wherein the optionally substituted aryl or heteroaryl is
2. The compound or salt of claim 1 , wherein the compound is a compound of the formula
3. The compound or salt of claim 1 , wherein the any one or more halogen is Br, Cl, F, or I independently of any other halogen.
4. The compound or salt of claim 1 , wherein any one or more alkyl is a C 1 -C 3 alkyl independently of any other alkyl.
5. The compound or salt of claim 1 , wherein any one or more aralkyl is ara(C 1 -C 3 -alkyl) independently of any other aralkyl.
6. The compound or salt of claim 1 , wherein the compound is
7. The compound or salt of claim 1 , wherein the compound is
8. The compound or salt of claim 1 , wherein the compound is
9. The compound or salt of claim 1 , wherein the compound is
10. The compound of 1 , wherein
R 1 is Cl,
R 2 , R, R 4 , R 5 , R 6 , R 8 , and R 9 are H,
R 7 is NHCOR 10 , and
R 10 is methyl.
11. The compound of 1 , wherein
R 1 is Cl,
R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , and R 9 are H, and
R 7 is CH═NR 10 .
12. A pharmaceutical composition comprising a compound or salt of claim 1 , together with a pharmaceutically acceptable excipient.
13. A method of treating Parkinson'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 in a patient comprising administering a compound, or combination of compounds of claim 1 , or a pharmaceutically acceptable salt thereof to the patient in an amount effective to activate chaperone-mediated autophagy (CMA) in the patient.
14. A compound having the structure
or a pharmaceutically acceptable salt thereof.
15. A compound having the structure
or, or a pharmaceutically acceptable salt thereof.