Compounds and methods to increase plasma HDL cholesterol levels and improve HDL functionality
View Patent ↗It has been discovered that certain selected ethers of probucol, and their pharmaceutically acceptable salts or prodrugs, are useful for increasing circulating HDL cholesterol. These compounds may also improve HDL functionality by (a) increasing clearance of cholesteryl esters, (b) increasing HDL-particle affinity for hepatic cell surface receptors or (c) increasing the half life of apoAI-HDL.
1. A compound of the formula:
wherein X=CH 2 C(O) 2 R, C(O) 2 R, or C(O)NR 1 R 2 ; n=1, 2, 3, 4, or 5; m=2, 3, 4, 5, 6, or 7; and
R, R 1 and R 2 are independently hydrogen, or alkyl, aryl, aralkyl, or alkaryl, which can be optionally substituted with one or more moieties selected from the group consisting of hydroxyl, carboxy, carboxamido, carboalkoxy, acyl, amino, halo, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, and phosphonate; or its pharmaceutically acceptable salt.
2. The compound of claim 1 , wherein X is C(O) 2 R.
3. The compound of claim 1 , wherein n is 1, 2, or 3.
4. The compound of claim 1 , wherein m is 3, 4, 5, or 6.
5. A method for increasing high density lipoprotein cholesterol level in a host comprising administering an effective amount of a compound of the formula:
wherein X=CH 2 C(O) 2 R, C(O) 2 R, or C(O)NR 1 R 2 ; n=1, 2, 3, 4, or 5; m=2, 3, 4, 5, 6, or 7; and
R, R 1 and R 2 are independently hydrogen, or alkyl, aryl, aralkyl, or alkaryl, which can be optionally substituted with one or more moieties selected from the group consisting of hydroxyl, carboxy, carboxamido, carboalkoxy, acyl, amino, halo, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, and phosphonate; or its pharmaceutically acceptable salt.
6. The method of claim 5 , wherein X is C(O) 2 R.
7. The method of claim 5 , wherein n is 1, 2, or 3.
8. The method of claim 5 , wherein m is 3, 4, 5, or 6.
9. A pharmaceutical composition for increasing plasma HDLc or improving HDL functionality in a subject comprising an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.