Compounds and methods of treating ocular disorders
A method of treating an ocular disorder in a subject associated with increased all-trans-retinal in an ocular tissue includes administering to the subject a therapeutically effective amount of a primary amine compound of formula (I); and pharmaceutically acceptable salts thereof.
1. A method of treating an ocular disorder in a subject associated with increased all-trans-retinal in an ocular tissue, the method comprising:
administering to the subject a therapeutically effective amount of a primary amine compound of formula (I):
wherein R 1 is a cyclic or polycyclic ring, wherein the ring is a substituted or unsubstituted aryl, heteroaryl, cycloalkyl, or heterocyclyl; wherein the ring of R 1 does not include a dimethyl substituent in the ortho position to the polyene chain;
n=1-3;
where R 2 , R 3 , R 4 , R 5 , R 6 , 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,
wherein, R 2 and R 4 may be linked to form a cyclic or polycyclic ring, wherein the ring is a substituted or unsubstituted aryl, heteroaryl, cycloalkyl, or heterocyclyl; and pharmaceutically acceptable salts thereof.
2. The method of claim 1 , the primary amine compound upon administration to the subject transiently sequestering all-trans-retinal in ocular tissue of a subject by forming a reversible Schiff-base with the all-trans-retinal, wherein the primary amine compound does not adversely affect normal retinoid cycle performance.
3. The method of claim 1 , the primary amine compound not inhibiting RPE65 enzymatic activity in the subject.
4. The method of claim 1 , the primary amine capable of serving as a substrate of enzymatic LRAT.
5. The method of claim 1 , the therapeutically effective amount of the primary amine compound comprising an amount effective to inhibit bright light-induced retinal damage in a Rdh8 −/− Abca4 −/− mouse.
6. The method of claim 1 , the primary amine compound when administered to a Rdh8 −/− Abca4 −/− mouse increasing the optical coherence tomography score of the mouse in comparison to untreated control animal.
7. The method of claim 1 , the primary amine compound being delivered to the subject by at least one of topical administration, systemic administration, intravitreal injection, and intraocular delivery.
8. The method of claim 1 , the primary amine being provided in an ocular preparation for sustained delivery.
9. The method of claim 1 , the ocular disorder comprising at least one of light induced retinal degeneration, macular degeneration, Stargardt's disease, and retinitis pigmentosa.
10. The method of claim 1 , the primary amine compound not causing night blindness in the subject.
11. The method of claim 1 , wherein the primary amine compound is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
12. A method of treating Stargardt disease in a subject, the method comprising:
administering to the subject a therapeutically effective amount of a primary amine compound of formula (I):
wherein R 1 is a cyclic or polycyclic ring, wherein the ring is a substituted or unsubstituted aryl, heteroaryl, cycloalkyl, or heterocyclyl; wherein the ring of R 1 does not include a dimethyl substituent in the ortho position to the polyene chain;
n=1-3;
where R 2 , R 3 , R 4 , R 5 , R 6 , 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,
wherein, R 2 and R 4 may be linked to form a cyclic or polycyclic ring, wherein the ring is a substituted or unsubstituted aryl, heteroaryl, cycloalkyl, or heterocyclyl; and pharmaceutically acceptable salts thereof.
13. The method of claim 12 , the primary amine compound upon administration to the subject transiently sequestering all-trans-retinal in ocular tissue of a subject by forming a reversible Schiff-base with the all-trans-retinal, wherein the primary amine compound does not adversely affect normal retinoid cycle performance.
14. The method of claim 12 , the primary amine compound not inhibiting RPE65 enzymatic activity in the subject.
15. The method of claim 12 , the primary amine capable of serving as a substrate of enzymatic LRAT.
16. The method of claim 12 , the therapeutically effective amount of the primary amine compound comprising an amount effective to inhibit bright light-induced retinal damage in a Rdh8 −/− Abca4 −/− mouse.
17. The method of claim 12 , the primary amine compound when administered to a Rdh8 −/− Abca4 −/− mouse increasing the optical coherence tomography score of the mouse in comparison to untreated control animal.
18. The method of claim 12 , the primary amine compound being delivered to the subject by at least one of topical administration, systemic administration, intravitreal injection, and intraocular delivery.
19. The method of claim 12 , the primary amine being provided in an ocular preparation for sustained delivery.
20. The method of claim 12 , the primary amine compound not causing night blindness in the subject.
21. The method of claim 12 , wherein the primary amine compound is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.