Use of metformin and analogs thereof to reduce RAN protein levels in the treatment of neurological disorders
View Patent ↗The present disclosure provides the use of compounds of Formulae (I), (II), (III), (III-A), and (III-B) (e.g., metformin) in treating a neurological disease associated with repeat expansions and/or RAN protein accumulation, reducing the level of one or more repeat associated non-ATG (RAN) proteins, and reducing the accumulation of RAN proteins in a subject and/or biological sample. Also provided is the use of compounds of Formulae (I), (II), (III), (III-A), and (III-B) (e.g., metformin) in inhibiting RAN protein translation in a subject and in a biological sample (e.g., cells, tissue). Also provided in the present disclosure are pharmaceutical compositions, Skits, and uses of compounds of Formulae (I), (II), (III), (III-A), and (III-B) (e.g., metformin) for treating diseases associated with repeat expansions. Exemplary diseases associated with repeat expansions include, but are not limited to, C90RFf72 amyotrophic lateral sclerosis (ALS), or C90RFf72 frontotemporal dementia; myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2); spinocerebellar ataxia; Huntington's disease; Fragile X Tremor Ataxia Syndrome (FXTAS); and Fragile XE syndrome (FRAXE).
1. A method of treating a neurological disease associated with repeat expansions in a subject in need thereof, the method comprising administering to the subject a compound of Formula (I):
or a pharmaceutically acceptable salt or tautomer thereof, wherein:
each instance of is a single bond or double bond, as valency permits;
each instance of R 2A is independently hydrogen, or substituted or unsubstituted C 1-6 alkyl;
R 3 is hydrogen or C 1-6 alkyl;
each instance of R 4 is independently hydrogen or C 1-6 alkyl, or absent, as valency permits;
each instance of R 6 is independently hydrogen or C 1-6 alkyl, or absent, as valency permits; and
R 7 is hydrogen or C 1-6 alkyl, or absent, as valency permits;
wherein the neurological disease is C9orf72 amyotrophic lateral sclerosis (ALS) or C9orf72 frontotemporal dementia (FTD).
2. The method of claim 1 , wherein the compound is of Formula (I-A):
or a pharmaceutically acceptable salt or tautomer thereof, wherein:
each instance of R 2A is independently hydrogen or substituted or unsubstituted C 1-6 alkyl.
3. The method of claim 1 , wherein the compound is of formula:
or a pharmaceutically acceptable salt or tautomer thereof.
4. The method of claim 1 , wherein at least one instance of R 2A is hydrogen or unsubstituted C 1-6 alkyl.
5. The method of claim 1 , wherein R 3 is hydrogen or methyl.
6. The method of claim 1 , wherein at least one instance of R 6 is hydrogen or methyl.
7. The method of claim 1 , wherein the compound is of formula:
or a pharmaceutically acceptable salt or tautomer thereof.
8. The method of claim 1 , wherein the neurological disease is C9orf72 amyotrophic lateral sclerosis (ALS).
9. The method of claim 1 , wherein the neurological disease is C9orf72 frontotemporal dementia (FTD).
10. The method of claim 1 , wherein R 4 is hydrogen or methyl.
11. The method of claim 1 , wherein R 7 is hydrogen or methyl.
12. The method of claim 1 , wherein the compound of Formula (I) is of the formula:
13. The method of claim 1 , wherein the compound of Formula (I) is of the formula:
14. The method of claim 1 , wherein at least one instance of R 2A is hydrogen.
15. The method of claim 1 , wherein at least one instance of R 2A is unsubstituted C 1-6 alkyl.
16. The method of claim 1 , wherein at least one instance of R 2A is methyl.