US 12,648,917 B2 · Use of metformin and analogs thereof to reduce RAN protein levels in the treatment of neurological disorders

Abstract

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, kits, 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, C9ORFf72 amyotrophic lateral sclerosis (ALS), or C9ORFf72 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).

Claims15

Dependent claims

A method of treating a neurological disease associated with repeat expansions in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount of a compound of Formula (I):

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein:
each instance of is a single bond or double bond, as valency permits;
each instance of R2A is independently hydrogen or substituted or unsubstituted C1-6 alkyl;
R3 is hydrogen or unsubstituted C1-6 alkyl;
each instance of R4 is independently hydrogen, unsubstituted C1-6 alkyl, or absent, as valency permits;
each instance of R6 is independently hydrogen, unsubstituted C1-6 alkyl, or absent, as valency permits;
and
R7 is hydrogen, unsubstituted C1-6 alkyl, or absent, as valency permits;
wherein the neurological disease associated with repeat expansions is spinocerebellar ataxia type 1, 2, 3, 6, 7, 8, 12, or 17.

6 more elements

Dependencies are inferred from the claim text.

Use of metformin and analogs thereof to reduce RAN protein levels in the treatment of neurological disorders

Life of this patent

Use of metformin and analogs thereof to reduce RAN protein levels in the treatment of neurological disorders

Life of this patent

Abstract

Claims15