Composition and methods of use of novel phenylalanine small organic compounds to directly modulate PCSK9 protein activity

1. A compound of Formula I:

wherein

R 3 is selected from the group consisting of H, C 1-6 alkyl, halo, haloalkyl, hydroxylalkyl, alkoxyl, and nitrile;

R 4 is selected from the group consisting of H and —OH;

R 5 is selected from the group consisting of branched alkyl, cycloalkyl, hydroxyalkyl, haloalkyl;

X 1 through X 5 are selected independently from the group CH, CR 1 , CR 2 , and N, wherein at most one of X 1 to X 5 is CR 1 and at most one of X 1 to X 5 is CR 2 , and wherein X 1 to X 5 are part of an aromatic or heteroaryl ring;

R 1 and R 2 are independently selected from the group consisting of C 1-6 alkyl, halo, —OH, and amino;

W is C, CH, or N, wherein when W is C then the dashed bonds are single bonds, and W and Y join together, along with the atoms to which they are attached, to form a 5 membered ring in which Y is CH 2 , and wherein when W is CH or N, then the dashed bonds are absent and Y is absent;

or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

2. A compound, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the compound is selected from:

(S)-3-([1,1′-biphenyl]-4-yl)-2-amino-N-isopropylpropanamide;

(S)-2-amino-3-(3-fluoro-4-(pyridin-4-yl)phenyl)-N-isopropylpropanamide;

(S)-2-amino-N-isopropyl-3-(3-methyl-4-(2-oxo-1,2-dihydropyridin-4-yl)phenyl)propanamide;

(S)-2-amino-3-(3′-hydroxy-2-methyl-[1,1′-biphenyl]-4-yl)-N-isopropylpropanamide;

(2S,3R)-2-amino-3-hydroxy-3-(5-(3-hydroxyphenyl)-4-methylpyridin-2-yl) -N-isopropylpropanamide;

(S)-2-amino-3-(5-(3-hydroxyphenyl)pyridin-2-yl)-N-isopropylpropanamide;

(S)-2-amino-3-(5-(3-hydroxyphenyl)-4-methylpyridin-2-yl)-N-isopropylpropanamide;

(S)-2-amino-3-(2′-fluoro-5′-hydroxy-2-methyl-[1,1′-biphenyl]-4-yl)-N-isopropylpropanamide;

(R)-2-amino-N-isopropyl-5-phenyl-2,3-dihydro-1H-indene-2-carboxamide;

(S)-3-([1,1′-biphenyl]-4-yl)-2-amino-N-((S)-1-(isopropylamino)-1-oxopropan-2-yl)propanamide;

(S)-3-([1,1′-biphenyl]-4-yl)-2-amino-N-((R)-1-(isopropylamino)-1-oxopropan-2-yl)propanamide;

(R)-2-((S)-3-([1,1′-biphenyl]-4-yl)-2-aminopropanamido)-N-ethyl-3-methylbutanamide;

(S)-3-([1,1′-biphenyl]-4-yl)-2-amino-N-((S)-1-(((S)-1-morpholino-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)propanamide;

(S)-2-amino-3-(3′-hydroxy-[1,1′-biphenyl]-4-yl)-N-((S)-1-(isopropylamino)-1-oxopropan-2-yl)propanamide;

(R)-2-amino-5-(3-hydroxyphenyl)-N-isopropyl-6-methyl-2,3-dihydro-1H-indene-2-carboxamide;

(S)-2-amino-N-isopropyl-3-(4-(2-oxo-1,2-dihydropyridin-4-yl)phenyl)propanamide;

(S)-2-amino-3-(3′-hydroxy-[1,1′-biphenyl]-4-yl)-N-isopropylpropanamide;

(S)-3-([1,1′-biphenyl]-4-yl)-2-amino-N-cyclopentylpropanamide;

(S)-3-([1,1′-biphenyl]-4-yl)-2-amino-N-((R)-1-phenylpropan-2-yl)propanamide;

(S)-3-([1,1′-biphenyl]-4-yl)-2-amino-N-((S)-1-phenylpropan-2-yl)propanamide;

(S)-2-amino-3-(2-cyano-[1,1′-biphenyl]-4-yl)-N-isopropylpropanamide;

(S)-2-amino-N-isopropyl-3-(2-methoxy-[1,1′-biphenyl]-4-yl)propanamide;

(S)-2-amino-N-isopropyl-3-(2-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)propanamide;

(S)-2-amino-3-(2′,3′-difluoro-[1,1′-biphenyl]-4-yl)-N-isopropylpropanamide;

(S)-2-amino-3-(2-ethyl-[1,1′-biphenyl]-4-yl)-N-isopropylpropanamide;

(S)-2-amino-3-(4-cyclohexylphenyl)-N-isopropylpropanamide;

(S)-2-amino-N-isopropyl-3-(4-(thiophen-2-yl)phenyl)propanamide;

and (S)-2-amino-3-(4-cyclopentylphenyl)-N-isopropylpropanamide.

3. A pharmaceutical composition comprising the compound of claim 1 , and a pharmaceutically acceptable carrier or excipient.

4. The pharmaceutical composition of claim 3 , wherein said pharmaceutical composition further comprises a second active ingredient.

5. The pharmaceutical composition of claim 4 , wherein said second active ingredient is selected from the group consisting of a statin, a cardiovascular drug, a metabolic drug, and an antihypertensive drug.

6. A method of modulating low density lipoprotein receptor internalization in a plurality of hepatocyte cells, comprising:

inducing a conformational shift in a PCSK9 protein, wherein said protein comprises a low density lipoprotein receptor binding site

by binding a compound of Formula I of claim 1 to a binding site that induces allosteric modulation in the PCSK9 protein;

wherein the plurality of hepatocyte cells comprise low density lipoproteins;

whereby the rate of low density lipoprotein receptor internalization by said plurality of hepatocytes is modulated by said conformational shift.

7. The method of claim 6 , whereby the rate of low density lipoprotein receptor internalization is increased.

8. A method of modulating a population of low density lipoprotein receptors in a plurality of hepatocyte cells, comprising:

inducing a conformational shift in a PCSK9 protein, wherein said protein comprises a low density lipoprotein receptor binding site

by binding a compound of Formula I of claim 1 to a binding site that induces allosteric modulation in the PCSK9 protein;

whereby the population of said low density lipoprotein receptors is modulated by said conformational shift.

9. The method of claim 8 , whereby the population of low density lipoprotein receptors is increased.

10. A method for reducing LDL levels in a mammal in need thereof by administering a pharmaceutical composition comprising a compound of claim 1 to said mammal.

11. A method for treating hypercholesterolemia in a mammal in need thereof by administering a pharmaceutical composition comprising a compound of claim 1 to said mammal.