Selective Glycosidase Inhibitors and Uses Thereof
AssigneeSimon Fraser University
InventorsDavid Jaro Vocadlo, Ernest John Mceachern
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Abstract
The invention provides compounds of Formula (I) for selectively inhibiting glycosidases, prodrugs of the compounds, and pharmaceutical compositions including the compounds or prodrugs of the compounds. The invention also provides methods of treating diseases and disorders related to deficiency or overexpression of O-GlcNAcase, accumulation or deficiency of O-GlcN Ac.
Claims30
A compound of Formula (I) or a pharmaceutically acceptable salt thereof:
- wherein
- X is O, S, or NR3;
- each R1 is independently a non-interfering substituent;
- R2 is NR32;
- wherein each R3 is optionally independently a non-interfering substituent,
- with the proviso that when X is O and each R1 is H or C(O)CH3, R2 excludes N(CH3)2.
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A method of selectively inhibiting an O-GlcNAcase in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof:
- wherein
- X is O, S, or NR3;
- each R1 is independently a non-interfering substituent;
- R2 is NR32;
- wherein each R3 is optionally independently a non-interfering substituent.
A method of elevating the level of O-GlcNAc in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof:
- wherein
- X is O, S, or NR3;
- each R1 is independently a non-interfering substituent;
- R2 is NR32;
- wherein each R3 is optionally independently a non-interfering substituent.
A method of treating a condition that is modulated by an O-GlcNAcase, in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof:
- wherein
- X is O, S, or NR3;
- each R1 is independently a non-interfering substituent;
- R2 is NR32;
- wherein each R3 is optionally independently a non-interfering substituent.
A method of treating a condition selected from the group consisting of a neurodegenerative disease, a tauopathy, cancer and stress, in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof:
- wherein
- X is O, S, or NR3;
- each R1 is independently a non-interfering substituent;
- R2 is NR32;
- wherein each R3 is optionally independently a non-interfering substituent.
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A method for screening for a selective inhibitor of an O-GlcNAcase, the method comprising:
- a) contacting a first sample with a test compound;
- b) contacting a second sample with a compound of Formula (I)
- wherein
- X is O, S, or NR3;
- each R1 is independently a non-interfering substituent;
- R2 is NR32;
- wherein each R3 is optionally independently a non-interfering substituent;
- c) determining the level of inhibition of the O-GlcNAcase in the first and second samples,
- wherein the test compound is a selective inhibitor of a O-GlcNAcase if the test compound exhibits the same or greater inhibition of the O-GlcNAcase when compared to the compound of Formula (I).
Dependencies are inferred from the claim text.