Selective glycosidase inhibitors and uses thereof
AssigneesMerck Sharp & Dohme Corp., Alectos Therapeutics Inc.
InventorsCraig A. Coburn, Kun Liu, Ernest J. McEacher, Changwei Mu, Harold G. Selnick, David J. Vocadlo, Yaode Wang, Zhongyong Wei, Yuanxi Zhou
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Abstract
The invention provides compounds 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-GlcNAc.
Claims27
A compound of Formula (I) or a pharmaceutically acceptable salt thereof:
- wherein
- each R1 is independently H or C1-6 acyl;
- both R2 groups are joined together with the nitrogen atom to which they are attached to form a ring, said ring optionally independently substituted from one up to the maximum number of substituents with one or more of:
- fluoro, OH, methyl, or OCH3;
- R3 is OR4 or NR42;
- and
- each R4 is independently selected from the group consisting of:
- H, C1-6 alkyl, C3-6 cycloalkyl, C2-6 alkenyl, C3-6 cycloalkenyl, C2-6 alkynyl, C1-6 acyl, or carbamoyl.
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A method of selectively inhibiting an O-GlcNAcase or of elevating the level of O-GlcNAc or 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
- each R1 is independently H or C1-6 acyl;
- both R2 groups are joined together with the nitrogen atom to which they are attached to form a ring, said ring optionally independently substituted from one up to the maximum number of substituents with one or more of:
- fluoro, OH, methyl, or OCH3;
- R3 is OR4 or NR42;
- and
- each R4 is independently selected from the group consisting of:
- H, C1-6 alkyl, C3-6 cycloalkyl, C2-6 alkenyl, C3-6 cycloalkenyl, C2-6 alkynyl, C1-6 acyl, or carbamoyl.
-17. (canceled)
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-30. (canceled)
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
- each R1 is independently H or C1-6 acyl;
- both R2 groups are joined together with the nitrogen atom to which they are attached to form a ring, said ring optionally independently substituted from one up to the maximum number of substituents with one or more of:
- fluoro, OH, methyl, or OCH3;
- R3 is OR4 or NR42;
- and
- each R4 is independently selected from the group consisting of:
- H, C1-6 alkyl, C3-6 cycloalkyl, C2-6 alkenyl, C3-6 cycloalkenyl, C2-6 alkynyl, C1-6 acyl, or carbamoyl;
- 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.