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.
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 consisting of H, and optionally substituted (C 1 -C 3 )-alkyl, (C 1 -C 3 )-alkoxyalkyl, aryloxyalkyl, (C 1 -C 3 )-alkylthioalkyl, arylthioalkyl, aryl, and heteroaryl; each R 3 is independently selected from the group consisting of H, halogen, (C 1 -C 3 )-alkyl, (C 1 -C 3 )-alkoxy, and optionally substituted aryl, or R 3 taken together with an adjacent R 3 forms an optionally substituted 5-7 membered aryl ring;
each R 4 is independently selected from the group consisting of H, halogen, (C 1 -C 3 ) alkyl and (C 1 -C 3 ) alkoxy;
R 5 is CONR 6 R 7 , wherein R 6 and R 7 are independently selected from the group consisting of H and optionally substituted aryl;
or a pharmaceutically acceptable salt or stereoisomer of the compound.
2. The method of claim 1 , comprising administering a therapeutically effective amount of a compound of the formula:
wherein R 1 is selected from the group consisting of H and CH 3 ;
R 3 is independently selected from the group consisting of H and (C 1 -C 3 )-alkoxy; and
one of R 6 and R 7 is H and the other is
wherein R 8 is selected from the group consisting of CO 2 H, CONHR 9 , 2-oxazole, 2-oxazoline, and 2-benzoxazole; R 9 is H or optionally substituted (C 1 -C 3 )-alkyl;
or a pharmaceutically acceptable salt or stereoisomer of the compound.
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
N-(4-{[4-(1,3-benzoxazol-2-yl)phenyl](methyl)carbamoyl}phenyl)-1-benzofuran-2-carboxamide (SBC-115,423);
N-(4-{[4-(1,3-benzoxazol-2-yl)phenyl]carbamoyl}phenyl)-1-benzofuran-2-carboxamide (SBC-115,337);
N-(4-{[4-(1,3-benzoxazol-2-yl)phenyl]carbamoyl}phenyl)-5-methoxy-3-methyl-1-benzofuran-2-carboxamide (SBC-115,418);
N-{4-[(4-carbamoylphenyl)carbamoyl]phenyl}-1-benzofuran-2-carboxamide (SBC-115,424);
N-(4-{[4-(4,5-dihydro-1,3-oxazol-2-yl)phenyl]carbamoyl}phenyl)-1-benzofuran-2-carboxamide (SBC-115,432);
N-(4-{[4-(1,3-oxazol-2-yl)phenyl]carbamoyl}phenyl)-1-benzofuran-2-carboxamide (SBC-115,433);
7-methoxy-3-methyl-N-(4-{[4-(1,3-oxazol-2-yl)phenyl]carbamoyl}phenyl)-1-benzofuran-2-carboxamide (SBC-115,445); and
pharmaceutically acceptable salts or stereoisomers thereof.
4. The method of claim 3 , wherein said compound is N-(4-{[4-(1,3-benzoxazol-2-yl)phenyl]carbamoyl}phenyl)-5-methoxy-3-methyl-1-benzofuran-2-carboxamide (SBC-115,418) or a pharmaceutically acceptable salt or stereoisomer thereof.
5. The method of claim 3 , wherein said compound is N-(4-{[4-(1,3-benzoxazol-2-yl)phenyl](methyl)carbamoyl}phenyl)-1-benzofuran-2-carboxamide (SBC-115,423) or a pharmaceutically acceptable salt or stereoisomer thereof.