Uridine phosphorylase (UPase) inhibitors for treatment of liver conditions
Methods of treating a subject for a liver condition, e.g., NAFLD, NASH, and/or DILI, are provided. Aspects of the methods include administering to the subject an effective amount of a UPase inhibitor, optionally in combination with a uridine active agent (e.g., uridine (UR), a UR pro-drug or a UR mimetic), such as supplemental uridine, to treat the subject for the liver condition. Also provided are compositions for use in practicing the subject methods.
1 . A method of treating a subject for a fibrosis-associated liver condition, the method comprising:
administering to a subject known to be suffering from a fibrosis-associated liver condition an effective amount of a 2,2′-anhydropyrimidine or derivative thereof to ameliorate fibrosis to treat the subject for the fibrosis-associated liver condition, wherein the 2,2′-anhydropyrimidine or derivative thereof is the only active agent administered to the subject.
2 . The method according to claim 1 , wherein the 2,2′-anhydropyrimidine or derivative thereof is a compound of formula (I):
or the pharmaceutically acceptable salts, solvates, hydrates, and prodrug forms thereof, and stereoisomers thereof;
wherein:
each R 1 , R 2 , R 3 and R 4 is independently selected from the group consisting of hydrogen, substituted or unsubstituted heteroatom, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, carbohydrate, nucleic acid, amino acid, peptide, dye, fluorophore and polypeptide.
3 . The method according to claim 2 , wherein each R 1 , R 2 , R 3 and R 4 is independently selected from the group consisting of hydrogen, hydroxyl, sulfyhydryl, amino, hydroxymethyl, methoxy, halogen, pseudohalogen, and a substituted or unsubstituted lower hydrocarbon containing 1 to 20 carbons.
4 . The method according to claim 2 , wherein the lower hydrocarbon is selected from the group consisting of alkyl, alkenyl, alkanoyl, aryl, aroyl, aralkyl and alkylamino, and esters thereof.
5 . The method according to claim 2 , wherein R 1 is hydrogen, fluorine, methyl, ethyl, propyl, benzyl, or 2-bromovinyl; R 2 is hydrogen, hydroxyl fluorine, methyl, ethyl, propyl, benzyl, benzoyl, benzoyloxy, or 2-bromovinyl; and each R 3 and R 4 is independently selected from the group consisting of hydroxyl and benzoyloxy.
6 . The method according to claim 5 , wherein R 1 is hydrogen or methyl; R 2 is hydrogen; and each R 3 and R 4 is independently selected from the group consisting of hydroxyl and benzoyloxy.
7 . The method according to claim 1 , wherein the 2,2′-anhydropyrimidine or derivative thereof is selected from the group consisting of: 2,2′-anhydro-5-methyluridine; 3′-O-benzoyl-2,2′-anhydrouridine; 3′-O-benzoyl-2,2′-anhydro-5-methyluridine; 5′-O-benzoyl-2,2′-anhydrouridine; and 5′-O-benzoyl-2,2′-anhydro-5-methyluridine.
8 . The method according to claim 7 , wherein the 2,2′-anhydropyrimidine or derivative thereof is 2,2′-anhydro-5-methyluridine.
9 . The method according to claim 7 , wherein the 2,2′-anhydropyrimidine or derivative thereof is 3′-O-benzoyl-2,2′-anhydro-5-methyluridine.
10 . The method according to claim 7 , wherein the 2,2′-anhydropyrimidine or derivative thereof is 5′-O-benzoyl-2,2′-anhydro-5-methyluridine.
11 . The method according to claim 1 , wherein the 2,2′-anhydropyrimidine or derivative thereof comprises a stereoisomer.
12 . The method according to claim 11 , wherein the stereoisomer is selected from the group consisting of 2,2′-anhydro-1-(β-D-arabinofuranosyl)-5-methyluracil; 3′-O-benzoyl-2,2′-anhydro-1-(β-D-arabinofuranosyl)-uracil; 3′-O-benzoyl-2,2′-anhydro-1-(β-D-arabinofuranosyl)-5-methyluracil; 5′-O-benzoyl-2,2′-anhydro-1-(β-D-arabinofuranosyl)-uracil; and 5′-O-benzoyl-2,2′-anhydro-1-(β-D-arabinofuranosyl)-5-methyluracil.
13 . The method according claim 1 , wherein the fibrosis-associated liver condition is selected from the group consisting of NAFLD, NASH and DILI.
14 . A method of treating a subject for a fibrosis-associated liver condition, the method comprising:
administering to a subject known to be suffering from a fibrosis-associated liver condition an effective amount of a 2,2′-anhydropyrimidine or derivative thereof in combination with a uridine (UR) active agent to ameliorate fibrosis to treat the subject for the fibrosis-associated liver condition, wherein the 2,2′-anhydropyrimidine or derivative thereof and the UR active agent are the only active agents administered to the subject.
15 . The method according to claim 14 , wherein the 2,2′-anhydropyrimidine or derivative thereof is a compound of formula (I):
or the pharmaceutically acceptable salts, solvates, hydrates, and prodrug forms thereof, and stereoisomers thereof;
wherein:
each R 1 , R 2 , R 3 and R 4 is independently selected from the group consisting of hydrogen, substituted or unsubstituted heteroatom, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, carbohydrate, nucleic acid, amino acid, peptide, dye, fluorophore and polypeptide.
16 . The method according to claim 14 , wherein the fibrosis-associated liver condition is selected from the group consisting of NAFLD, NASH and DILI.
17 . The method according to claim 13 , wherein the fibrosis-associated liver condition is DILI.
18 . The method according to claim 13 , wherein the fibrosis-associated liver condition is NASH.
19 . The method according to claim 13 , wherein the fibrosis-associated liver condition is NAFLD.
20 . The method according to claim 16 , wherein the fibrosis-associated liver condition is DILI.
21 . The method according to claim 16 , wherein the fibrosis-associated liver condition is NASH.
22 . The method according to claim 16 , wherein the fibrosis-associated liver condition is NAFLD.
23 . The method according to claim 14 , wherein the 2,2′-anhydropyrimidine or derivative thereof is selected from the group consisting of: 2,2′-anhydro-5-methyluridine; 3′-O-benzoyl-2,2′-anhydrouridine; 3′-O-benzoyl-2,2′-anhydro-5-methyluridine; 5′-O-benzoyl-2,2′-anhydrouridine; and 5′-O-benzoyl-2,2′-anhydro-5-methyluridine.
24 . A method of treating a subject for a fibrosis-associated liver condition, the method comprising:
administering to a subject known to be suffering from a fibrosis-associated liver condition an effective amount of a 2,2′-anhydropyrimidine or derivative thereof, or an effective amount of a 2,2′-anhydropyrimidine or derivative thereof in combination with a uridine (UR) active agent, to treat the subject for the fibrosis-associated liver condition;
wherein the only active agent administered to the subject is the 2,2′-anhydropyrimidine or derivative thereof, or the 2,2′-anhydropyrimidine or derivative thereof in combination with the UR active agent; and
wherein the 2,2′-anhydropyrimidine or derivative thereof is selected from the group consisting of: 2,2′-anhydro-5-methyluridine; 3′-O-benzoyl-2,2′-anhydrouridine; 3′-O-benzoyl-2,2′-anhydro-5-methyluridine; 5′-O-benzoyl-2,2′-anhydrouridine; and 5′-O-benzoyl-2,2′-anhydro-5-methyluridine.
25 . The method according to claim 24 , wherein the subject is administered the 2,2′-anhydropyrimidine or derivative thereof.
26 . The method according to claim 24 , wherein the subject is administered the 2,2′-anhydropyrimidine or derivative thereof in combination with the UR active agent.
27 . The method according to claim 24 wherein the 2,2′-anhydropyrimidine or derivative thereof is 2,2′-anhydro-5-methyluridine.
28 . The method according to claim 24 , wherein the 2,2′-anhydropyrimidine or derivative thereof is 3′-O-benzoyl-2,2′-anhydro-5-methyluridine.
29 . The method according to claim 24 , wherein the 2,2′-anhydropyrimidine or derivative thereof is 5′-O-benzoyl-2,2′-anhydro-5-methyluridine.