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Selective glycosidase inhibitors and uses thereof

a glycosidase inhibitor and selective technology, applied in the field of selective glycosidase inhibitors, can solve the problems of complex use of non-selective inhibitors in studying the physiological role of one particular enzyme, hyperphosphorylation of tau, and disruption of normal functions of tau, so as to increase the level of o-glcnac

Inactive Publication Date: 2014-07-31
ALECTOS THERAPEUTICS INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention provides compounds that can selectively inhibit glycosidases, particularly O-GlcNAcase, and prodrugs of these compounds. The compounds can be used to treat diseases related to deficiencies or overexpression of O-GlcNAcase, such as Alzheimer's disease, ALS, and cancer. The compounds have a specific structure that allows them to selectively inhibit O-GlcNAcase and increase the level of O-GlcNAc. The invention also provides pharmaceutical compositions and methods of using the compounds for treating these diseases.

Problems solved by technology

In AD patients, however, tau becomes hyperphosphorylated, disrupting its normal functions, forming PHFs and ultimately aggregating to form NFTs.
However, a major challenge in developing inhibitors for blocking the function of mammalian glycosidases, including O-GlcNAcase, is the large number of functionally related enzymes present in tissues of higher eukaryotes.
Accordingly, the use of non-selective inhibitors in studying the cellular and organismal physiological role of one particular enzyme is complicated because complex phenotypes arise from the concomitant inhibition of such functionally related enzymes.
NAG-thiazoline has been found to be a potent inhibitor of family 20 hexosaminidases,90,109 and more recently, the family 84 O-GlcNAcases.108 Despite its potency, a downside to using NAG-thiazoline in a complex biological context is that it lacks selectivity and therefore perturbs multiple cellular processes.

Method used

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  • Selective glycosidase inhibitors and uses thereof
  • Selective glycosidase inhibitors and uses thereof
  • Selective glycosidase inhibitors and uses thereof

Examples

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examples

[0144]The following examples are intended to illustrate embodiments of the invention and are not intended to be construed in a limiting manner.

examples 1 & 2

(3aR,5R,6S,7R,7aR)-5-(acetoxymethyl)-2-(azetidin-1-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diyl diacetate (2) and (3aR,5R,6S,7R,7aR)-2-(azetidin-1-yl)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol (3)

[0145]

(3aR,5R,6S,7R,7aR)-5-(acetoxymethyl)-2-(azetidin-1-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diyl diacetate (2)

[0146]A solution of azetidine hydrochloride (12 g, 129 mmol) and (3R,4R,5S,6R)-6-(acetoxymethyl)-3-isothiocyanato-tetrahydro-2H-pyran-2,4,5-triyl triacetate (48 g, 123 mmol) in dichloromethane (500 mL) was treated with triethylamine (18.7 g, 185 mmol) for 1 h at room temperature, and followed by addition oftrifluoroacetic acid (56.2 g, 493 mmol). The reaction mixture was stirred overnight at room temperature, and then quenched by aqueous sodium bicarbonate. The organic layer was separated, dried over anhydrous MgSO4, and condensed under vacuum to give a residue, which was purified by a silica gel column, eluted with 1% ...

example 15

(3aR,5R,6S,7R,7aR)-2-(azetidin-1-yl)-5-((cyclopentylamino)methyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol (5)

[0150]

((3aR,5R,6S,7R,7aR)-2-(azetidin-1-yl)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)methyl 4-methylbenzenesulfonate (4)

[0151]A solution of (3aR,5R,6S,7R,7aR)-2-(azetidin-1-yl)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol (5.0 g, 19 mmol) and triethylamine (3.88 g, 38 mmol) in DMF (50 mL) was treated with 4-methylbenzene-1-sulfonyl chloride (4.4 g, 23 mmol) overnight at room temperature. The reaction mixture was quenched by water (100 mL), extracted with dichloromethane (3×80 mL), washed with brine (3×50 mL), dried over anhydrous magnesium sulfate, and concentrated under vacuum to give a residue, which was purified by a silica gel column eluted with 1%-5% methanol in dichloromethane to give crude compound 4 as a light yellow solid (1.0 g). This material was employed in the next step without further purification...

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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.

Description

FIELD OF THE INVENTION[0001]This application relates to compounds which selectively inhibit glycosidases and uses thereof.BACKGROUND OF THE INVENTION[0002]A wide range of cellular proteins, both nuclear and cytoplasmic, are post-translationally modified by the addition of the monosaccharide 2-acetamido-2-deoxy-β-D-glucopyranoside (β-N-acetylglucosamine) which is attached via an β-glycosidic linkage.1 This modification is generally referred to as O-linked N-acetylglucosamine or O-GlcNAc. The enzyme responsible for post-translationally linking β-N-acetylglucosamine (GlcNAc) to specific serine and threonine residues of numerous nucleocytoplasmic proteins is O-GlcNAc transferase (OGT).2-5 A second enzyme, known as glycoprotein 2-acetamido-2-deoxy-β-D-glucopyranosidase (O-GlcNAcase)6,7 removes this post-translational modification to liberate proteins making the O-GlcNAc-modification a dynamic cycle occurring several times during the lifetime of a protein.8 [0003]O-GlcNAc-modified protein...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D513/14
CPCC07D513/14C07D513/04C07H9/06C07H13/04C07H13/12C07H15/18C12Q1/48G01N2500/02
Inventor COBURN, CRAIG A.LIU, KUNMCEACHERN, ERNEST J.MU, CHANGWEISELNICK, HAROLD G.VOCADLO, DAVID J.WANG, YAODEWEI, ZHONGYONGZHOU, YUANXI
Owner ALECTOS THERAPEUTICS INC
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