Anti-proprotein convertase subtilisin kexin type 9 (anti-PCSK9) compounds and methods of using the same in the treatment and/or prevention of cardiovascular diseases
Disclosed are compounds that modulate the physiological action of the proprotein convertase subtilisin kexin type 9 (PCSK9), as well as therapeutic methods for use of such compounds to reduce LDL-cholesterol levels and/or for the treatment and/or prevention of cardiovascular disease (CVD), including treatment of hypercholesterolemia. Examples of compounds include thiadiazole, isoxazole, 1,2,4-triazole, thiazole, indole, pyrazole, and pyrrolinone derivatives.
1. A method for treating hypercholesterolemia, and/or at least one symptom of dyslipidemia, atherosclerosis, CVD or coronary heart disease in a patient in need of said treatment, the method comprising administering to said patient a therapeutically effective amount of a compound of the formula:
wherein R 1 is selected from the group of optionally substituted cycloalkyl, cycloalkyloxy, aryloxy, aralkoxy, heterocycle, heterocycloalkoxy, heteroaryl, and heteroaralkoxy;
R 2 is selected from the group of H and optionally substituted lower alkyl, cycloalkyl, aryl, heterocycle, and heteroaryl;
R 4 is selected from the group of H, lower alkyl, OH, SH, NH 2 , halo, CN, carboxyl, and carboxamido;
wherein X 1 and Y 1 and are the same or different and each represents hydrogen, or a lower alkyl substituent and Z 1 is substituted at the para-position of the phenyl ring of said formula, and Z 1 represents an alkoxy substituent in which the alkyl moiety of said alkoxy substituent is substituted with an optionally substituted aryl group;
and s is an integer from 1 to 4;
or a pharmaceutically acceptable salt or stereoisomer of said compound.
2. The method of claim 1 , wherein the alkyl moiety of said alkoxy substituent is selected from the group consisting of benzyl, 2-methyl benzyl, 3-methyl benzyl and phenethyl.
3. A method for treating hypercholesterolemia, and/or at least one symptom of dyslipidemia, atherosclerosis, CVD or coronary heart disease in a patient in need of said treatment, the method comprising administering to said patient a therapeutically effective amount of a compound selected from the group consisting of:
4-[4-(benzyloxy)-3-methylbenzoyl]-3-hydroxy-1-[3-(morpholin-4-yl)propyl]-5-(pyridin-4-yl)-2,5-dihydro-1H-pyrrol-2-one (SBC-115,076)
3-hydroxy-4-{4-[(3-methylphenyl)methoxy]benzoyl}-1-[3-(morpholin-4-yl)propyl]-5-(pyridin-4-yl)-2,5-dihydro-1H-pyrrol-2-one (SBC-115,177)
4-[4-(benzyloxy)-2-methylbenzoyl]-3-hydroxy-1-[3-(morpholin-4-yl)propyl]-5-(pyridin-3-yl)-2,5-dihydro-1H-pyrrol-2-one (SBC-115,178)
4-[4-(benzyloxy)-3-methylbenzoyl]-3-hydroxy-1-[3-(morpholin-4-yl)propyl]-5-(pyridin-3-yl)-2,5-dihydro-1H-pyrrol-2-one (SBC-115,181)
4-[4-(benzyloyx)-2-methylbenzoyl]-3-hydroxy-1-[3-(morpholin-4-yl)propyl]-5-(pyridine-4-yl)-2,5-dihydro-1H-pyrrol-2-one (SBC-115,180), or a pharmaceutically acceptable salt or stereoisomer of said compound.
4. The method of claim 3 , wherein said compound is 4-[4-(benzyloxy)-3-methylbenzoyl]-3-hydroxy-1-[3-(morpholin-4-yl)propyl]-5-(pyridin-4-yl)-2,5-dihydro-1H-pyrrol-2-one (SBC-115,076):
5. The method of claim 1 , wherein the compound administered is a compound of said formula wherein R 1 is selected from the group consisting of optionally substituted heterocycle and heteroaryl and s is 3.