Compounds and methods for myotonic dystrophy therapy
The invention provides rationally designed multi-targeting therapeutic agents for myotonic dystrophy type 1 (DM1), an incurable neuromuscular disease that originates in an abnormal expansion of CTG repeats (CTG exp ) in the DMPK gene. The rationally designed small molecules target the DM1 pathobiology in three distinct ways: (1) binding the expanded trinucleotide repeat, CTG exp , and inhibiting its transcription to the toxic CUG exp RNA, (2) binding the CUG exp RNA and releasing sequestered muscleblind-like protein (MBNL1), and (3) cleaving the toxic CUG exp in an RNase-like manner. Importantly, the compounds can reduce the levels of CUG exp in DM1 model cells and reverse two separate CUG exp -induced phenotypes of DM1.
1. A compound of Formula I:
wherein
n is 0, 1, or 2;
A is a direct bond or —C(═O)NH—;
X 1 and X 2 are each independently —H, —C(═O)NHCH 2 CH 2 N(CH 2 CH 2 NH 2 ) 2 , or a moiety of Formula C1:
wherein R 1 and R 2 are each independently —H or a moiety of Formula C2:
wherein at least one of X 1 and X 2 is not —H;
or a salt or solvate thereof.
2. The compound of claim 1 wherein X 1 is H.
3. The compound of claim 1 wherein X 1 is —C(═O)NHCH 2 CH 2 N(CH 2 CH 2 NH 2 ) 2 .
4. The compound of claim 1 wherein X 1 is a moiety of Formula C1.
5. The compound of claim 4 wherein R 1 is H.
6. The compound of claim 4 wherein R 1 is a moiety of Formula C2.
7. The compound of claim 4 wherein R 1 and R 2 are each H.
8. The compound of claim 4 wherein R 1 and R 2 are each a moiety of Formula C2.
9. The compound of claim 4 wherein R 1 is H and R 2 is a moiety of Formula C2.
10. The compound of claim 1 wherein X 2 is H.
11. The compound of claim 1 wherein X 2 is —C(═O)NHCH 2 CH 2 N(CH 2 CH 2 NH 2 ) 2 .
12. The compound of claim 1 wherein X 2 is a moiety of Formula C1.
13. The compound of claim 12 wherein R 1 is H.
14. The compound of claim 12 wherein R 1 is a moiety of Formula C2.
15. The compound of claim 12 wherein R 1 and R 2 are each H.
16. The compound of claim 12 wherein R 1 and R 2 are each a moiety of Formula C2.
17. The compound of claim 12 wherein R 1 is H and R 2 is a moiety of Formula C2.
18. A compound of Formula II:
wherein
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;
X 1 and X 2 are each independently —H, —C(═O)NHCH 2 CH 2 N(CH 2 CH 2 NH 2 ) 2 , or a moiety of Formula C1:
wherein R 1 and R 2 are each independently —H or a moiety of Formula C2:
and
wherein at least one of X 1 and X 2 is not —H;
or a salt or solvate thereof.
19. The compound:
or a salt or solvate thereof.
20. 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 19 , thereby reducing the symptoms of the myotonic dystrophy.