Compounds and methods of treating retinal degeneration

1. A method of treating retinal degeneration in a subject, comprising:

administering to the subject a therapeutically effective amount of a compound having a formula selected from the group consisting of

(I):

wherein X 1 is CH 2 or C═O, wherein X 2 is O;

and;

wherein R 1 and R 2 are each independently selected from the group consisting of hydrogen, a substituted or unsubstituted cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein at least one of R 1 or R 2 is a substituted or unsubstituted thiophene;

and pharmaceutically acceptable salts thereof.

2. The method of claim 1 , the compound comprising the formula (III):

wherein R 2 and R 6 are each individually hydrogen, a substituted or unsubstituted C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 3 -C 20 aryl, heteroaryl, heterocycloalkenyl containing from 5-6 ring atoms (wherein from 1-3 of the ring atoms is independently selected from N, NH, N(C 1 -C 6 alkyl), NC(O)(C 1 -C 6 alkyl), O, and S), C 6 -C 24 alkaryl, C 6 -C 24 aralkyl, halo, —Si(C 1 -C 3 alkyl) 3 , hydroxyl, sulfhydryl, C 1 -C 24 alkoxy, C 2 -C 24 alkenyloxy, C 2 -C 24 alkynyloxy, C 5 -C 20 aryloxy, acyl, acyloxy, C 2 -C 24 alkoxycarbonyl, C 6 -C 20 aryloxycarbonyl, C 2 -C 24 alkylcarbonato, C 6 -C 20 arylcarbonato, carboxy, carboxylato, carbamoyl, C 1 -C 24 alkyl-carbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, C 1 -C 24 alkyl amino, C 5 -C 20 aryl amino, C 2 -C 24 alkylamido, C 6 -C 20 arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C 1 -C 24 alkylsulfanyl, arylsulfanyl, C 1 -C 24 alkylsulfinyl, C 5 -C 20 arylsulfinyl, C 1 -C 24 alkylsulfonyl, C 5 -C 20 arylsulfonyl, phosphono, phosphonato, phosphinato, phospho, or phosphino or combinations thereof;

and pharmaceutically acceptable salts thereof.

3. The method of claim 1 , the compound comprising the formula (IV):

wherein R 1 and R 7 are each individually hydrogen, a substituted or unsubstituted C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 3 -C 20 aryl, heteroaryl, heterocycloalkenyl containing from 5-6 ring atoms (wherein from 1-3 of the ring atoms is independently selected from N, NH, N(C 1 -C 6 alkyl), NC(O)(C 1 -C 6 alkyl), O, and S), C 6 -C 24 alkaryl, C 6 -C 24 aralkyl, halo, —Si(C 1 -C 3 alkyl) 3 , hydroxyl, sulfhydryl, C 1 -C 24 alkoxy, C 2 -C 24 alkenyloxy, C 2 -C 24 alkynyloxy, C 5 -C 20 aryloxy, acyl, acyloxy, C 2 -C 24 alkoxycarbonyl, C 6 -C 20 aryloxycarbonyl, C 2 -C 24 alkylcarbonato, C 6 -C 20 arylcarbonato, carboxy, carboxylato, carbamoyl, C 1 -C 24 alkyl-carbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, C 1 -C 24 alkyl amino, C 5 -C 20 aryl amino, C 2 -C 24 alkylamido, C 6 -C 20 arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C 1 -C 24 alkylsulfanyl, arylsulfanyl, C 1 -C 24 alkylsulfinyl, C 5 -C 20 arylsulfinyl, C 1 -C 24 alkylsulfonyl, C 5 -C 20 arylsulfonyl, phosphono, phosphonato, phosphinato, phospho, or phosphino or combinations thereof;

and pharmaceutically acceptable salts thereof.

4. The method of claim 1 , wherein the compound is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

5. The method of claim 1 , wherein compound is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

6. The method of claim 1 , the retinal degeneration comprising inherited retinal degeneration associated with rhodopsin mutations.

7. The method of claim 1 , wherein the retinal degeneration is selected from the group consisting of Leber congenital amaurosis, Stargardt disease, and retinitis pigmentosa.

8. The method of claim 7 , the retinitis pigmentosa comprising autosomal dominate retinitis pigmentosa associated with a P23H RHO mutation.

9. The method of claim 1 , the therapeutically effective amount of the compound is an amount required to inhibit photoreceptor cell death in the subject.

10. The method of claim 1 , the therapeutically effective amount of the compound is an amount effective to inhibit bright light-induced retinal degeneration in a Rdh8 −/− Abca4 −/− mouse.

11. The method of claim 1 , wherein the compound stabilizes P23H rod opsin mutant proteins.

12. The method of claim 1 , wherein the compound promotes rod photoreceptor cell homeostasis in the subject.

13. The method of claim 1 , wherein the compound upon administration to the subject mobilizes the P23H opsin from the endoplasmic reticulum to the plasma membrane of photoreceptor cells.

14. The method of claim 1 , wherein the compound inhibits early endoplasmic reticulum associated protein degradation (ERAD) pathway in the subject.

15. The method of claim 1 , the compound being delivered to the subject by at least one of topical administration, systemic administration, intravitreal injection, and intraocular delivery.

16. The method of claim 15 , wherein the compound is administered to the subject systemically.

17. The method of claim 1 , wherein the activity of the compound is not affected negatively when photoreceptor cells of the subject are exposed to light.

18. The method of claim 1 , further comprising administering a histone deacetylase (HDAC) inhibitor in combination with the compound.