Bisamidinium-based inhibitors for the treatment of myotonic dystrophy
The invention provides compounds, compositions and therapeutic methods. The compounds and compositions can be used for the treatment of myotonic dystrophy. The compounds can selectively bind to CUG repeats in RNA, or to CTG repeats in DNA, and inhibit replication of the nucleic acids. RNA-targeted therapeutic agents for the treatment of myotonic dystrophy type 1 (DM1) are described. In one embodiment, two bisamidinium ligands are linked using “click” chemistry to form a heterodimer that is a potent inhibitor of the MBNL1-rCUG exp complex (K I =25±8 nM), is relatively non-toxic to HeLa cells, dissolves nuclear foci, corrects >80% of the IR misregulated alternative splicing in DM1 model cells (1 μM), and shows improvement of disease phenotypes in a DM1 Drosophila model.
1. A compound of Formula I:
wherein
R 1 is H, —(C 1 -C 5 )alkyl-C≡CH, or —(C 1 -C 5 )alkyl-N 3 ;
R 2 is H, —(C 1 -C 5 )alkyl-C≡CH, —(C 1 -C 5 )alkyl-N 3 , or a moiety of Formula IA:
wherein
each p is independently 1-8; and
each L is independently —(C 3 -C 5 )alkylene-, —(C 2 -C 5 )alkylene- interrupted by one oxygen, 1,3-cyclopenylene, 1,3-cyclohexylene, or 1,4-cyclohexylene;
provided that one of R 1 and R 2 is not H;
or a salt or solvate thereof.
2. The compound of claim 1 wherein R 1 is H, propargyl, -ethyl-C≡CH, -propyl-C≡CH, -ethyl-N 3 , -propyl-N 3 , or -butyl-N 3 .
3. The compound of claim 1 wherein R 2 is H, propargyl, -ethyl-C≡CH, -propyl-C≡CH, -ethyl-N 3 , -propyl-N 3 , or -butyl-N 3 .
4. The compound of claim 1 wherein R 1 is H and R 2 is propargyl or —CH 2 CH 2 —C≡CH.
5. The compound of claim 1 wherein R 1 is H and R 2 is —(C 2 -C 4 )alkyl-N 3 .
6. The compound of claim 1 wherein R 1 and R 2 are each propargyl or —CH 2 CH 2 —C≡CH.
7. The compound of claim 1 wherein R 1 and R 2 are each —(C 2 -C 4 )alkyl-N 3 .
8. The compound of claim 1 wherein R 2 is a moiety of Formula IA and R 1 is H, —(C 1 -C 4 )alkyl-C≡CH, or —(C 1 -C 4 )alkyl-N 3 .
9. The compound of claim 8 wherein R 1 is H.
10. The compound of claim 8 wherein each p is independently 1, 2, or 3.
11. The compound of claim 8 wherein each L of the moiety of Formula IA is propylene, butylene, or pentylene.
12. The compound of claim 1 wherein the substituents on the central phenyl ring of Formula I are in a para orientation.
13. The compound of claim 1 wherein each L of the compound of Formula I or the moiety of Formula IA, independently of one another, is propylene, butylene, or pentylene.
14. The compound of claim 1 that is a compound of Formula II:
wherein R 1 and R 2 are each independently propargyl, —CH 2 CH 2 —C≡CH, or —CH 2 CH 2 CH 2 —N 3 ; or a salt or solvate thereof.
15. The compound of claim 1 that is a compound of Formula II:
wherein R 1 is H and R 2 is propargyl, —CH 2 CH 2 —C≡CH, or propyl-N 3 ; or a salt or solvate thereof.
16. The compound of claim 1 wherein the compound is:
wherein p is 1 or 2; or a salt or solvate thereof.
17. A pharmaceutical composition comprising the compound claim 1 in combination with a pharmaceutically acceptable diluent, carrier, or excipient.
18. A method of reducing the symptoms of myotonic dystrophy comprising administering to a patient having myotonic dystrophy an effective amount of a compound of claim 1 , thereby reducing the symptoms of the myotonic dystrophy.
19. The method of claim 18 wherein the myotonic dystrophy is myotonic dystrophy type 1 (DM1).
20. The method of claim 18 wherein the symptoms of myotonic dystrophy reduced by the administration are one or more of myopathy, myotonia, progressive muscle atrophy, cataracts, cardiac defect, and insulin dependent diabetes.
21. A compound of Formula I:
wherein
R 1 is H, —(C 1 -C 5 )alkyl-C≡CH, or —(C 1 -C 5 )alkyl-N 3 ;
R 2 is a moiety of Formula IA:
wherein
each p is independently 1-8; and
each L is independently —(C 3 -C 5 )alkylene-, —(C 2 -C 5 )alkylene- interrupted by one oxygen, 1,3-cyclopenylene, 1,3-cyclohexylene, or 1,4-cyclohexylene;
or a salt or solvate thereof.
22. A method of reducing the symptoms of myotonic dystrophy comprising administering to a patient having myotonic dystrophy an effective amount of a compound of claim 21 , thereby reducing the symptoms of the myotonic dystrophy.