Prodrugs of Deoxynucleosides for Treatment of Mitochondrial Diseases Caused by Unbalanced Nucleotide Pools
Deoxynucleotide prodrugs and methods of their use for treatment of diseases characterized by unbalanced nucleotide pools such as MPV17 and deoxyguanosine kinase deficiency are provided herein.
1 . A method for treating a mitochondrial depletion disease or disorder chosen from MPV17 and dGK deficiency in a subject in need thereof comprising administering to the subject a therapeutically effective amount of at least one prodrug of Formula I:
wherein Base refers to guanine or guanine with a protected amino group;
R 1 is selected from the group consisting of optionally substituted acyl, optionally substituted O-linked amino acid,
X, Y and Z are each independently selected from O and S;
R 2 , R 3 and R 4 are each independently selected from hydrogen, optionally substituted C 1-24 alkyl, optionally substituted C 2-24 alkenyl, optionally substituted C 2-24 alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 3-6 cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryl(C 1-6 ) alkyl,
or R 2 and R 3 can be taken together to form a cyclic moiety;
R 5 , R 6 and R 7 are each independently selected from optionally substituted C 1-24 alkyl, optionally substituted C 2-24 alkenyl, optionally substituted C 2-24 alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 3-6 cycloalkenyl, NR 20 R 21 , optionally substituted N-linked amino acid, optionally substituted N-linked amino acid ester;
R 8 , R 9 , R 11 and R 12 are each independently selected from hydrogen, optionally substituted C 1-24 alkyl and optionally substituted aryl;
R 10 and R 11 are each independently selected from hydrogen, optionally substituted C 1-24 alkyl and optionally substituted aryl, an optionally substituted O-C 1-24 alkyl, an optionally substituted —O-aryl, an optionally substituted —O-heteroaryl, an optionally substituted —O-monocyclic hetercyclyl;
R 14 , R 15 and R 19 are each independently selected from hydrogen, an optionally substituted C 1-24 alkyl and an optionally substituted aryl;
R 16 and R 17 are each independently selected from —CN, optionally substituted C 2-8 organylcarbonyl, C 2-8 alkoxycarbonyl and C 2-8 organylaminocarbonyl;
R 18 is selected from hydrogen, optionally substituted C 1-24 alkyl, optionally substituted C 2-24 alkenyl, optionally substituted C 2-24 alkynyl; optionally substituted C 3-6 cycloalkyl and optionally substituted C 3-6 cycloakenyl;
R 20 and R 21 are each independently selected from hydrogen, optionally substituted C 1-24 alkyl, optionally substituted C 2-24 alkenyl, optionally substituted C 2-24 alkynyl; optionally substituted C 3-6 cycloalkyl and optionally substituted C 3-6 cycloakenyl; and
n, m and p are each independently selected from 0, 1, 2, or 3.
2 . The method of claim 1 , wherein the prodrug is a compound of Formula Ia:
wherein each of R 1 , R 2 and R 3 are independently selected from hydrogen, optionally substituted C 1-24 alkyl, optionally substituted C 2-24 alkenyl, optionally substituted C 2-24 alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 3-6 cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted aryl(C 1-6 ) alkyl.
3 . The method of claim 2 , wherein R 1 is aryl, R 2 is C 1-24 alkyl and R 3 is C 1-24 alkyl.
4 . A method for treating a mitochondrial depletion disease or disorder chosen from MPV17 and dGK deficiency in a subject in need thereof comprising administering to the subject a therapeutically effective amount of at least one prodrug of Formula II
wherein Base refers to guanine or guanine with a protected amino group;
X is selected from S and O; and
R 22 is selected from —O − , —OH, —O-alkyl, optionally substituted C 1-6 alkoxy,
optionally substituted N-linked amino acid and optionally substituted N-linked amino acid ester;
wherein R 8 , R 9 , R 11 and R 12 are each independently selected from hydrogen, optionally substituted C 1-24 alkyl and optionally substituted aryl;
R 10 and R 13 are each independently selected from hydrogen, optionally substituted C 1-24 alkyl and optionally substituted aryl, an optionally substituted —O-C 1-24 alkyl, an optionally substituted —O-aryl, an optionally substituted —O-heteroaryl, an optionally substituted —O-monocyclic hetercyclyl; and
R 14 and R 15 are each independently selected from hydrogen, an optionally substituted C 1-24 alkyl and an optionally substituted aryl; and
n, m and p are each independently selected from 0, 1, 2, or 3.
5 . The method of claim 4 , wherein the prodrug is a compound of Formula IIa:
wherein R is C 1-4 alkyl.
6 . A method for treating a mitochondrial depletion disease or disorder chosen from MPV17 and dGK deficiency in a subject in need thereof comprising administering to the subject a therapeutically effective amount of at least one prodrug of Formula III:
wherein Base refers to an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group;
R 1 and R 2 are independently selected from hydrogen, phosphate; straight chained, branched or cyclic alkyl; acyl; CO-alkyl, CO-alkoxyalkyl; CO-aryloxyalkyl, CO-substituted aryl, sulfonate ester; alkylsulfonyl; arylsulfonyl; aralkylsulfonyl; a lipid; a phospholipid; an amino acid; a carbohydrate; a peptide and cholesterol.
7 . The method of claim 6 , wherein the prodrug is a compound of Formula IIIa:
wherein R is the side chain of an amino acid.
8 . The method of claim 6 , wherein the prodrug is a compound of Formula IIIb:
wherein Base refers to an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group.
9 . The method of claim 1 wherein the at least one prodrug is:
10 . The method of claim 6 , wherein a second prodrug is administered, and wherein the Base of the second prodrug is cytosine.
11 . The method of claim 10 , wherein the weight ratio of the at least one prodrug of Formula III to the second prodrug is 95/5, 90/10, 85/15, 80/20, 75/25, 70/30, 65/35, 60/40, 55/45 or 50/50.
12 . The method of claim 6 , wherein the prodrug is administered in the form of a pharmaceutical composition.
13 . The method of claim 6 , wherein the method of administration is oral.
14 . The method of claim 6 , wherein the dose administered is from about 200 mg/kg/day to about 1,000 mg/kg/day.
15 . The method of claim 6 , wherein the prodrug or composition comprising the same is administered at least once per day.
16 . The method of claim 6 , wherein Base refers to guanine.
17 . The method of claim 6 , wherein Base refers to guanine with a protected amino group.
18 . The method of claim 4 , wherein the at least one prodrug is:
19 . The method of claim 6 , wherein the at least one prodrug is selected from the following: