Retinal derivatives and methods for the use thereof for the treatment of visual disorders
Compositions of and methods for using synthetic retinal derivatives as retinoid replacements and opsin agonists are provided.
1. A retinyl ester selected from the group consisting of a 9-cis-retinyl ester of Formula I and an 11-cis-retinyl ester of Formula II, wherein A is CH 2 OR and —R, when taken together with the adjacent oxygen is a carboxylate radical of a C 2 to C 10 polycarboxylic acid:
wherein the ester substituent is selected from the group consisting of oxalate, malonate, succinate, citrate, ketoglutarate, fumarate, malate, glutarate, adipate, pimelate, suberate, azelate, sebacate, and oxaloacetate;
wherein the retinyl ester is a pro-drug that, when administered to a subject, is metabolically transformed into a retinal capable of binding opsin.
2. The retinyl ester of claim 1 , which is a 9-cis-retinyl ester of Formula I.
3. The retinyl ester of claim 2 , wherein the 9-cis-retinyl ester is 9-cis-retinyl succinate, 9-cis-retinyl citrate, 9-cis-retinyl ketoglutarate, 9-cis-retinyl fumarate, 9-cis-retinyl malate or 9-cis-retinyl oxaloacetate.
4. The retinyl ester of claim 3 , wherein the 9-cis-retinyl ester is 9-cis-retinyl succinate.
5. The retinyl ester of claim 1 , which is an 11-cis-retinyl ester of Formula II.
6. The retinyl ester of claim 5 , wherein the 11-cis-retinyl ester is 11-cis-retinyl succinate, 11-cis-retinyl citrate, 11-cis-retinyl ketoglutarate, 11-cis-retinyl fumarate, 11-cis-retinyl malate or 11-cis-retinyl oxaloacetate.
7. A retinyl ester selected from the group consisting of a 9-cis-retinyl ester of Formula I:
and an 11-cis-retinyl ester of Formula II:
wherein A is CH 2 OR and R forms a retinyl ester, wherein the ester substituent comprises a carboxylate radical of a C 3 to C 10 polycarboxylic acid;
wherein the ester substituent is selected from the group consisting of malonate, succinate, citrate, ketoglutarate, fumarate, malate, glutarate, adipate, pimelate, suberate, azelate, sebacate, and oxaloacetate; and
wherein the retinyl ester is a pro-drug that, when administered to a subject, is metabolically transformed into a retinal capable of binding opsin.
8. The retinyl ester of claim 7 , which is a 9-cis-retinyl ester of Formula I.
9. The retinyl ester of claim 8 , wherein the 9-cis-retinyl ester is 9-cis-retinyl succinate, 9-cis-retinyl citrate, 9-cis-retinyl ketoglutarate, 9-cis-retinyl fumarate, 9-cis-retinyl malate or 9-cis-retinyl oxaloacetate.
10. The retinyl ester of claim 9 , wherein the 9-cis-retinyl ester is 9-cis-retinyl succinate.
11. The retinyl ester of claim 7 , which is an 11-cis-retinyl ester of Formula II.
12. The retinyl ester of claim 11 , wherein the 11-cis-retinyl ester is 11-cis-retinyl succinate, 11-cis-retinyl citrate, 11-cis-retinyl ketoglutarate, 11-cis-retinyl fumarate, 11-cis-retinyl malate or 11-cis-retinyl oxaloacetate.