The present disclosure provides non-naturally occurring polyphenol compounds that upregulate the expression of Apolipoprotein A-I (ApoA-I). The disclosed compositions and methods can be used for treatment and prevention of cardiovascular disease and related disease states, including cholesterol or l
The present disclosure provides non-naturally occurring polyphenol compounds that upregulate the expression of Apolipoprotein A-I (ApoA-I). The disclosed compositions and methods can be used for treatment and prevention of cardiovascular disease and related disease states, including cholesterol or lipid related disorders, such as, e.g., atherosclerosis.
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1. A method for increasing expression of ApoA-I in a mammal comprising administering a therapeutically effective amount of a compound of Formula I: wherein: X is O;Y is CO;R1, R3, R4, R5, R6, R8, R9, and R17 are each independently selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino
1. A method for increasing expression of ApoA-I in a mammal comprising administering a therapeutically effective amount of a compound of Formula I: wherein: X is O;Y is CO;R1, R3, R4, R5, R6, R8, R9, and R17 are each independently selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone;R2 is selected from alkoxy, aryloxy, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone;R7 is selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone;R10 is selected from alkyl, aryloxy, alkenyl, alkynyl, amide, amino, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone;each W is independently selected from C and N, wherein if W is N, then p is 0 and if W is C, then p is 1;at least one W is N;Z1 and Z3 are each a single bond; andZ2 is a double bond;and pharmaceutically acceptable salts and hydrates thereof. 2. The method of claim 1, wherein the therapeutically effective amount of the compound of Formula I is administered with a pharmaceutically acceptable carrier in a pharmaceutically acceptable composition. 3. The method of claim 1, further comprising treating a cardiovascular, cholesterol or lipid related disorder. 4. A method for increasing expression of ApoA-I in a mammal comprising administering a therapeutically effective amount of a compound selected from: 5,7-Difluoro-2-(4hydroxyl-phenyl)-chromen-4-one,2-(3,5-Difluoro-4-hydroxyphenyl)chromen-4-one,2-(4-Hydroxy-3,5-dimethylphenyl)chromen-4-one,2-(5-Methoxy-pyridin-2-yl)-chromen-4-one,2-(5-Hydroxy-pyridin-2-yl)-chromen-4-one,2-(6-Hydroxy-pyridin-3-yl)-chromen-4-one,2-(4-Methoxy-phenyl)-thiochromen-4-one,2-(4-Hydroxy-phenyl)-thiochromen-4-one,2-(4-Hydroxyphenyl)-3-methyl-4H-chromen-4-one,4-(6-Bromo-4-oxo-4H-chromen-2-yl)-2-fluorophenyl acetate,1-(2-Nitro-4-methoxy-phenyl)-chromen-4-one,2-(4-Hydroxy-2-nitrophenyl)chromen-4-one,2-(2-Amino-4-methoxy-phenyl)-chromen-4-one,2-(2-Amino-4-hydroxy-phenyl)-chromen-4-one,N[5-Hydroxy-2-(4-oxo-4H-chromen-2-yl)-phenyl]acetamide,6-Hydroxy-2-(4-hydroxymethylphenyl)chromen-4-one,2-(2-Fluoro-4-hydroxyphenyl)chromen-4-one,2-(4-Hydroxyphenyl)-8-nitro-4H-chromen-4-one,2-(4-Hydroxyphenyl)-8-methoxy-4H-chromen-4-one,2-(4-Hydroxyphenyl)-5,7-dimethoxy-4H-chromen-4-one,2-(3-Bromo-4-hydroxyphenyl)-4H-chromen-4-one,2-(4-Hydroxyphenyl)-4-oxo-4H-chromene-6-carbonitrile,2-(4-Methoxy-phenyl)-chromen-4-one,2-(3-Fluoro-4-hydroxyphenyl)chromen-4-one,2-(4-Hydroxyphenyl)-4-oxo-4H-chromene-6-sulfonic acid,6-Hydroxymethyl-2-(4-hydroxyphenyl)chromen-4-one,6-((Dimethylamino)methyl)-2-(4-hydrophenyl)-4H-chromen-4-one,8-Hydroxy-2-(4-hydroxy-phenyl)-chromen-4-one,2-(4-Hydroxy-phenyl)-chromen-4-one,7-Hydroxy-2-(4-hydroxy-phenyl)-chromen-4-one,5-Hydroxy-2-(4-hydroxy-phenyl)-chromen-4-one,5,7-Djihydroxy-2-(4-hydroxy-phenyl)-chromen-4-one,5,7-Dihydroxy-2-phenyl-chromen-4-one,5-Hydroxy-2-phenyl-chromen-4-one,2-(4-Acetoxy-phenyl)-thiochromen-4-one,2-(4-Acetoxy-phenyl)-1,1-dioxo-1H-1λ6-thiochromen-4-one,2-(4-Hydroxy-phenyl)-1,1-dioxo-1H-1λ6-thiochromen-4-one,5,7-Dimethoxy-2-(4′-hydroxy-phenyl)-quinolin-4-one,5,7-Dihydroxy-2-(4-hydroxy-phenyl)-quinolin-4-one,2-(4-Hydroxy-phenyl)-pyrano[3,2-b]pyridin-4-one,2-(4-Methoxyphenyl)-4H-pyrano[2,3-b]pyridine-4-one,2-(4-Hydroxy-phenyl)-pyrano[2,3-b]pyridin-4-one,2-(4-(2-Hydroxyethoxy)phenyl)-4H-pyrano[2,3-b]pyridine-4-one,2-(3-Fluoro-4-hydroxyphenyl)pyrano[2,3-b]pyridine-4-one,2-(4-Hydroxy-3-methylphenyl)-4H-pyrano[2,3-b]pyridine-4-one,4-(4-Oxo-4H-pyrano[2,3-b]pyridine-2-yl)benzonitrile,2-(3-Chloro-4-hydroxyphenyl)-4H-pyrano[2,3-b]pyridine-4-one,2-(3-Bromo-4-hydroxyphenyl)-4H-pyrano[2,3-b]pyridin-4-one,2-(4-Hydroxy-3-methoxyphenyl)-4H-pyrano[2,3-b]pyridine-4-one,2-(4-Hydroxy-phenyl)-pyrano[2,3-c]pyridin-4-one,2-(4-hydroxy-phenyl)-pyrano[3,2-c]pyridin-4-one,2-(2-(4-Hydroxyphenyl)-4-oxo-4H-chromen-3-yl)acetonitrile,3-(Hydroxymethyl)-2-(4-hydroxyphenyl)-4H-chromen-4-one,2-(4-Hydroxyphenyl)-3-(methoxymethyl)-4H-chromen-4-one,3-(4-Hydroxyphenyl)-2H-isoquinolin-1-one,3-(3-Fluoro-4-hydroxyphenyl)-5-methoxyisoquinolin-1(2H)-one,2-Fluoro-4-(5-methoxy-1-(methylamino)-isoquinolin-3-yl)phenol,4-Naphthalen-2-yl-phenol,6-Naphthalen-2-yl-pyridin-3-ol,3-(4-Hydroxyphenyl)-naphthalene-1-ol,4-lsoquinolin-3-yl-phenol,4-(1,6-Naphthyridin-7-yl)phenol,2-(4-Hydroxy-phenyl)-[1,4]naphthoquinone,4-(Benzo[b][1,4]dioxin-2-yl)phenyl acetate,4-(Benzo[b][1,4]dioxin-2-yl)phenol,4-(4H-Chromen-2-yl)-phenol,2-(4-Hydroxyphenyl)benzo[e][1,3]oxazin-4-one,6-Naphthalen-2-yl-pyridin-3-ol,2-(4-Ethoxycarbonyloxy-phenyl)-4-oxo-4H-quinoline-1-carboxylic acid ethyl ester,Nicotinic acid 4-(4-oxo-4H-chromen-2-yl)-phenyl ester,Acetic acid 4-(4-oxo-4H-chromen-2-yl)-phenyl ester,4-(4-oxo-4H-pyrano[2,3-b]pyridine-2-yl)phenyl acetate,2-Amino-5-guanidino-pentanoic acid 4-(4-oxo-4H-chromen-2-yl)phenyl ester,4-(Isoquinolin-3-yl)phenyl 2-amino-5-guanidinopentanoate,4-(1-Oxo-1,2-dihydroisoquinolin-3-yl)phenyl 2-amino-5-guanidinopentanoate, and2-(4-(Nicotinoyloxy)phenyl)-4-oxo-4H-chromene-5,7-diyl dinicotinate. 5. A method for increasing expression of ApoA-I in a mammal comprising administering a therapeutically effective amount of the compound 4-isoquinolin -3-yl-phenol. 6. A method for increasing expression of ApoA-I in a mammal comprising administering a therapeutically effective amount of a compound of Formula VII: wherein: X is O;Y is CO;R1, R2, R3, R5, R6, R7, R8, R9, R10 and R17 are each independently selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone, ortwo adjacent substituents selected from R1, R2, R3, R5, R6, R7, R8, R9, and R10 are connected in a 5 or 6-membered ring to form a bicyclic aryl or bicyclic heteroaryl;Z1 and Z3 are single bonds, and Z2 is a double bond;and pharmaceutically acceptable salts and hydrates thereof. 7. The method of claim 6, wherein the compound of Formula I is 2-(4-hydroxy-phenyl)-pyrano[2,3-b]pyridin-4-one. 8. The method of claim 6, further comprising treating a cardiovascular, cholesterol or lipid related disorder.
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