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US 2017/0290806 A1Published application
PCSK9 Inhibitors and Methods of Use Thereof
AssigneeTemple University of the Commonwealth System of Higher Education
InventorsMagid Abou-Gharbia, Wayne E. Childers
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Abstract
The present invention relates to compositions and methods for treating lipid disorders in a subject. In one embodiment, the compositions of the present invention can be used to inhibit protease proprotein convertase subtilisin-like kexin type 9 (PCSK9). In another embodiment, the compositions of the present invention can be used to disrupt the protein-protein interaction between PCSK9 and low-density lipoprotein receptor (LDLR).
Claims20
A composition comprising a compound of Formula I:
- wherein in Formula (I):
- R1 is selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 alkenyl, C1-6 alkynyl, C1-6 haloalkyl, optionally substituted aryl, and optionally substituted alkylaryl;
- R2 is selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 alkenyl, C1-6 alkynyl, C1-6 haloalkyl, optionally substituted aryl, and optionally substituted alkylaryl, or R1 and R2 are optionally taken together with the atoms to which they are bound to form a ring containing 3 to 7 atoms, optionally containing a nitrogen, oxygen, or sulfur atom;
- X1 is selected from the group consisting of NR3COR4 and NR3SO2R4
- X2 is selected from the group consisting of hydrogen and C1-6 alkyl, or X1 and X2 are optionally taken together to form an optionally substituted aromatic six membered ring optionally containing a nitrogen atom;
- X3 is selected from the group consisting of CONR3R4 and SO2NR3R4;
- R3 at each occurrence is independently selected from the group consisting of hydrogen and C1-6 alkyl;
- R4 at each occurrence is independently selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 alkenyl, C1-6 alkynyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl, or R3 and R4 are optionally taken together with the atoms to which they are bound to form a ring containing 3 to 7 atoms.
5 more elements
A composition comprising a compound of Formula (IV):
- wherein in Formula (IV),
- n is an integer from 1 to 6;
- R is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl;
- R1a, R1b, R1c, and R1d are at each occurrence independently selected from the group consisting of hydrogen, halogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkenyl, optionally substituted C1-6 alkynyl, optionally substituted C1-6 haloalkyl, optionally substituted C3-7 cycloalkyl, optionally substituted C1-6 alkoxy, cyano, nitro, OR2, SR3, SO2R3, NR4aR4b, NR4aCOR5, NR4aCONR4aR4b, NR4aCOOR6, SO2NR4aR4b, and NR4aSO2R6;
- X is selected from the group consisting of oxygen, sulfur, NR4a, NCOR5, NCONR4aR4b, NCOOR6, and NR4aSO2R3;
- X1 is selected from the group consisting of N and CR1d;
- X2 is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl;
- R2 at each occurrence is independently selected from the group consisting of hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkenyl, optionally substituted C1-6 alkynyl, optionally substituted C1-6 haloalkyl, optionally substituted C3-7 cycloalkyl, optionally substituted aryl, COR5, CONR4aR4b, SO2NH2, and SO2R3;
- R3 at each occurrence is independently selected from the group consisting of hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkenyl, optionally substituted C1-6 alkynyl, optionally substituted C1-6 haloalkyl, optionally substituted C3-7 cycloalkyl, and optionally substituted aryl;
- R4a and R4b at each occurrence are independently selected from the group consisting of hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkenyl, optionally substituted C1-6 alkynyl, optionally substituted C1-6 haloalkyl, optionally substituted C3-7 cycloalkyl, and optionally substituted aryl;
- R5 at each occurrence is independently selected from the group consisting of hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkenyl, optionally substituted C1-6 alkynyl, optionally substituted C1-6 haloalkyl, optionally substituted C3-7 cycloalkyl, and optionally substituted aryl;
- and
- R6 at each occurrence is independently selected from the group consisting of optionally substituted C1-6 alkyl, optionally substituted C1-6 alkenyl, optionally substituted C1-6 alkynyl, optionally substituted C1-6 haloalkyl, optionally substituted C3-7 cycloalkyl, and optionally substituted aryl.
10 more elements
Dependencies are inferred from the claim text.