Aminoglycosides and uses thereof in treating genetic disorders
A new class of pseudo-trisaccharide aminoglycosides having an alkyl group at the 5″ position, exhibiting efficient stop codon mutation readthrough activity, low cytotoxicity and high selectivity towards eukaryotic translation systems are provided. Also provided are pharmaceutical compositions containing the same, and uses thereof in the treatment of genetic disorders, as well as processes of preparing these aminoglycosides. The disclosed aminoglycosides can be represented by the general formula I: or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of alkyl, cycloalkyl and aryl; and all other variables and features are as described in the specification.
1. A compound having the general formula I:
or a pharmaceutically acceptable salt thereof,
wherein:
R1 is selected from the group consisting of alkyl, cycloalkyl and aryl;
R2 is hydrogen or (S)-4-amino-2-hydroxybutyryl (AHB);
R3 is selected from the group consisting of hydrogen, alkyl, cycloalkyl and aryl; and
a stereo-configuration of each of position 6′ and position 5″ is independently an R configuration or an S configuration.
2. The compound of claim 1 , wherein R1 is alkyl.
3. The compound of claim 2 , wherein said alkyl is methyl.
4. The compound of claim 1 , wherein R2 and R3 are each hydrogen.
5. The compound of claim 1 , wherein R2 is AHB and R3 is hydrogen.
6. The compound of claim 1 , wherein R2 is hydrogen and R3 is alkyl.
7. The compound of claim 6 , wherein said alkyl is methyl.
8. The compound of claim 1 , wherein R2 is AHB and R3 is alkyl.
9. The compound of claim 8 , wherein said alkyl is methyl.
10. The compound of claim 1 , being selected from the group consisting of:
11. The compound of claim 1 , characterized by a ratio of IC50 translation inhibition in eukaryotes to IC50 translation inhibition in prokaryotes lower than 15.
12. The compound of claim 11 , wherein said ratio is lower than 1.
13. The compound of claim 1 , characterized by a MIC in Gram-negative bacteria higher than 200 μM and a MIC in Gram-positive bacteria higher than 20 μM.
14. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
15. The pharmaceutical composition of claim 14 , being packaged in a packaging material and identified in print, in or on said packaging material, for use in the treatment of a genetic disorder associated with a premature stop codon mutation and/or a protein truncation phenotype, said genetic disorder being selected from the group consisting of cystic fibrosis (CE), Duchenne muscular dystrophy (DMD), ataxia-telangiectasia, Hurler syndrome, hemophilia A, hemophilia B, Usher syndrome and Tay-Sachs.
16. The pharmaceutical composition of claim 14 , wherein R1 is alkyl.
17. The pharmaceutical composition of claim 16 , wherein said alkyl is methyl.
18. The pharmaceutical composition of claim 14 , wherein R2 and R3 are each hydrogen.
19. The pharmaceutical composition of claim 14 , wherein R2 is AHB and R3 is hydrogen.
20. The pharmaceutical composition of claim 14 , wherein R2 is hydrogen and R3 is alkyl.
21. The pharmaceutical composition of claim 14 , wherein R2 is AHB and R3 is alkyl.
22. The pharmaceutical composition of claim 15 , wherein said genetic disorder is cystic fibrosis.
23. A method for treating a genetic disorder associated with a premature stop codon mutation and/or a protein truncation phenotype, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claim 1 , wherein said genetic disorder being selected from the group consisting of cystic fibrosis (CF), Duchenne muscular dystrophy (DMD), ataxia-telangiectasia, Hurler syndrome, hemophilia A, hemophilia B, Usher syndrome and Tay-Sachs.
24. The method of claim 23 , wherein said genetic disorder is cystic fibrosis.
25. The method of claim 23 , wherein R1 is alkyl.
26. The method of claim 25 , wherein said alkyl is methyl.
27. The method of claim 23 , wherein R2 and R3 are each hydrogen.
28. The method of claim 23 , wherein R2 is AHB and R3 is hydrogen.
29. The method of claim 23 , wherein R2 is hydrogen and R3 is alkyl.
30. The method of claim 23 , wherein R2 is AHB and R3 is alkyl.
31. A process of preparing the compound of claim 1 , the process comprising:
(a) providing a donor compound having the general Formula II:
wherein:
R1 is selected from the group consisting of alkyl, cycloalkyl and aryl;
R4 is hydrogen or a donor amino-protecting group;
R5 is a donor amino-protecting group if R4 is hydrogen or hydrogen if R4 is a donor amino-protecting group;
each of HPd is a donor hydroxyl-protecting group; and
L is a leaving group;
(b) coupling said donor compound with an acceptor compound having the general formula III
wherein:
the dashed line indicates an R configuration or an S configuration;
R3 is selected from the group consisting of hydrogen, alkyl, cycloalkyl and aryl;
R6 is an acceptor amino-protecting group or (S)-4-azido-2-O-acetyl-1-butyryl;
HPa is an acceptor hydroxyl-protecting group; and
APa is an acceptor amino-protecting group; and
(c) removing each of said amino-protecting group and said hydroxyl-protecting group, thereby obtaining the compound.
32. The process of claim 31 , wherein said leaving group is trichloroacetimidate.
33. The process of claim 31 , wherein said donor hydroxyl-protecting group is O-benzoyl and said donor amino-protecting group is azido.
34. The process of claim 31 , wherein said acceptor hydroxyl-protecting group is O-acetyl and said acceptor amino-protecting group is azido.
35. The compound of claim 1 , being:
36. The compound of claim 1 , being:
37. The compound of claim 1 , being:
38. The compound of claim 1 , being:
39. The compound of claim 1 , being:
40. The compound of claim 1 , being:
41. The compound of claim 1 , being:
42. The compound of claim 1 , being: