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Glucoimidazole and polyhydroxycyclohexenyl amine derivatives to treat gaucher disease

a technology of glucoimidazole and phca, which is applied in the field of glucoimidazole (giz) and phca derivatives, can solve the problems of lack of specificity, difficult or inappropriate clinical use, complex protein folding, etc., and achieve the effect of enhancing the activity of gcas

Inactive Publication Date: 2005-06-23
AMICUS THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0021] The present invention also provide a method of stabilizing in mammalian cell the GCase by contacting the cell with a compound of Formula I or Formula II in an amount effective to stabilize the GCase.

Problems solved by technology

In vivo, protein folding is complicated, because the combination of ambient temperature and high protein concentration stimulates the process of aggregation, in which amino acids normally buried in the hydrophobic core interact with their neighbors non-specifically.
The high dosage of this class of compounds required for efficacy makes them difficult or inappropriate to use clinically, although they are useful for the biochemical examination of folding defect of a protein intracellularly.
They also lack specificity.
However, these inhibitors are either not specific enough or not potent enough towards to the GCase and not suitable for the treatment of Gaucher disease.
Although the inhibitors described by Panday were potent, they lack specificity for GCase.

Method used

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  • Glucoimidazole and polyhydroxycyclohexenyl amine derivatives to treat gaucher disease
  • Glucoimidazole and polyhydroxycyclohexenyl amine derivatives to treat gaucher disease
  • Glucoimidazole and polyhydroxycyclohexenyl amine derivatives to treat gaucher disease

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of GIZ Derivatives

a. (5R,6R,7S,8S)-6,7,8-Tris(benzyloxy)-5-[(benzyloxy)methyl]-2-(1-octynyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine

[0177] (5R,6R,7S,8S)-6,7,8-Tris(benzyloxy)-5-[(benzyloxy)methyl]-2-iodo-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine as described by Panday in Helv. Chim. Acta., 83, 58-79 (2000), (300 mg, 0.437 mmol) is combined with [Pd(PPh3)4] (0.252 mg, 0.22 mmol), Et3N (0.27 ml), CuI (8 mg, 0.04 mmol), and 1-octynye (0.19 ml, 1.31 mmol) in DMF (7.5 ml) and is stirred at 80° C. for 7 hours. The reaction mixture is diluted with ether (100 ml) and washed with water and then aq. sat. NaCl. The organic layer is dried over Na2SO4 and evaporated using a rotovap. Purification by flash chromatography using CH2Cl2 as the eluent gives the title compound as brown syrup. 1H NMR (300 MHz, CDCl3): δ7.43-7.14 (m, 21H), 5.15 (d, 1H, J=12 Hz), 4.86-4.75 (m, 4H), 4.62 (d, 1H, J=11.4 Hz), 4.50-4.44 (m, 3H), 4.20-4.16 (m, 1H), 4.10-4.07 (m, 1H), 3.84-3.78 (m, 2H), 3.73-3.70 (...

example 2

Inhibitory Activities of Glucoimidazole Derivatives Against GCase

[0181] Methods. The enzyme activity was assayed with 4-methylumbelliferyl β-glucoside (final concentration 3 mM) as substrate in Reaction Buffer consisting 0.25% sodium taurocholate, 0.1% Triton X-100 in McIlvaine buffer (0.1M citrate and 0.2M phosphate buffer) at pH 5.2. The compounds were added to each reaction mixture individually at the final concentration indicated. After incubation with the diluted human GCase at 37° C. for 30 min, the reaction was stopped by addition of 0.2 M glycine buffer, pH 10.8, the released 4-methylumbelliferone was determined by a fluoremeter at excitation wavelength of 355 nm and emission wavelength at 460 nm, respectively. The relative enzyme activity was calculated as a percentage to those of reactions without inhibitors. IC50 was calculated using Prism sigmoid plot.

[0182] Results. GIZ and 2-PE-GIZ were reported to be potent inhibitors for β-glucosidases (Panday et al., Helvetica Chi...

example 3

Chaperone Activity of GIZ for GCase in Gaucher Cells

[0183] Methods. Fibroblasts established from Gaucher patients with N370S / N370S mutation were cultured in DMEM medium supplemented with 10% fetal bovine serum and antibiotics at 37° C. under 5% CO2. The GIZ was added into the culture medium at the final concentrations for 4 days prior to the assay. After washing the cells with phosphate-buffered saline, the cells were harvested and homogenized in the presence of 0.25% (w / v) sodium taurocholate and 0.1% (v / v) Triton X-100 in McIlvaine buffer (pH 5.2, Reaction Buffer), and 10 μl of the lysate was used for the determination of residual enzyme activity. The activity of the GCase was determined with 3 mM 4-MU-β-Glc in the Reaction Buffer at 37° C. for 1 hr as conduritol B epoxide (CBE)-sensitive activity in parallel assays without or with pre-incubation with CBE at 1.25 mM for 30 min at room temperature. Protein concentrations in the cell lysates were determined using micro BCA protein ...

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Abstract

The present invention provides glucoimidazole (GIZ) and polyhydroxycyclohexenyl amine (PHCA) derivatives, methods of making them, and methods of use where the GIZ and PHCA derivatives have a short, flexible linker emanating from the corresponding position of the ring oxygen in a pyranose; and a lipophilic moiety connected to the linker and pharmaceutically acceptable salts thereof. More particularly, the present invention further provides a method for treating individuals having Gaucher disease by administering the novel GIZ or PHCA derivatives as “active-site specific chaperones” for the mutant glucocerebrosidase associated with the disease.

Description

[0001] This application claims priority to provisional application 60 / 519,496 filed Nov. 12, 2003, herein incorporated by reference.FIELD OF THE INVENTION [0002] The present invention provides novel glucoimidazole (GIZ) and polyhydroxy-cyclohexenyl amine (PHCA) derivatives having a short, flexible linker emanating from the corresponding position of the ring oxygen in a pyranose; and a lipophilic moiety connected to the linker and pharmaceutically acceptable salts thereof. The present invention further provides a method for treating individuals having Gaucher disease by administering the novel GIZ or PHCA derivatives as “active-site specific chaperones” for the mutant glucocerebrosidase associated with the disease. BACKGROUND OF THE INVENTION Protein Folding [0003] Proteins are synthesized in the cytoplasm, and the newly synthesized proteins are secreted into the lumen of the endoplasmic reticulum (ER) in a largely unfolded state. In general, protein folding is governed by the princ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61KA61K31/437A61K31/445A61K31/454A61K31/4745A61K31/50A61K31/501A61K48/00A61P43/00C07D211/40C07D471/02C07D471/04
CPCC07D487/04A61P1/16A61P19/00A61P25/00A61P3/06A61P43/00A61P7/06
Inventor FAN, JIAN-QIANGZHU, XIAOXIANGSHETH, KAMLESH
Owner AMICUS THERAPEUTICS INC
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