Second-Generation Iminoxylitol-Based Pharmacological Chaperones for the Treatment of Gaucher Disease

被引：63

作者：

Oulaidi, Farah ^{[1
,2
]}

Front-Deschamps, Sophie ^{[1
,2
]}

Gallienne, Estelle ^{[1
,2
]}

Lesellier, Eric ^{[1
,2
]}

Ikeda, Kyoko ^{[3
]}

Asano, Naoki ^{[4
]}

Compain, Philippe ^{[5
,6
]}

Martin, Olivier R. ^{[1
,2
]}

机构：

[1] Univ Orleans, ICOA, UMR 6005, F-45067 Orleans, France

[2] CNRS, F-45067 Orleans, France

[3] Hokuriku Univ, Fac Pharmaceut Sci, Kanazawa, Ishikawa 9201181, Japan

[4] BioApply Co Ltd, Kanazawa, Ishikawa 9200942, Japan

[5] Univ Strasbourg, SYBIO, UMR 7509, F-67087 Strasbourg, France

[6] CNRS, Ecole Europeenne Chim Polymeres & Mat, F-67087 Strasbourg, France

来源：

CHEMMEDCHEM | 2011年 / 6卷 / 02期

关键词：

drug design; gaucher disease; glycosidase inhibitors; iminosugars; pharmacological chaperone; LYSOSOMAL STORAGE DISORDERS; SUBSTRATE REDUCTION THERAPY; MUTANT ENZYME-ACTIVITY; BETA-GLUCOSIDASE; HIGHLY POTENT; N-BUTYLDEOXYNOJIRIMYCIN; RATIONAL DESIGN; IMINO SUGARS; INHIBITORS; DERIVATIVES;

D O I：

10.1002/cmdc.201000469

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of O-alkyl iminoxylitol derivatives was synthesized and evaluated as beta-glucocerebrosidase (GCase) inhibitors. This structure-activity study shows a dramatic influence of the position of the alkyl chain (alpha-C1, O2, O3, or O4) on human GCase inhibition. Remarkably, 1,2-shift of the alkyl chain from C1 to O2 was found to maintain high inhibitory potency toward GCase as well as chaperone activity at sub-inhibitory concentration (10 nm). Removal of the stereogenic center at the pseudo-anomeric position led to shorter and more practical synthetic sequences. 2-O-Alkyl iminoxylitol derivatives constitute a new promising class of leads for the treatment of Gaucher disease by means of pharmacological chaperone therapy.

引用

页码：353 / 361

页数：9

共 72 条

[1] Biochemistry of glycosphingolipid storage disorders: implications for therapeutic intervention [J].

Aerts, JM ;

Hollak, C ;

Boot, R ;

Groener, A .

PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES, 2003, 358 (1433) :905-914

[2]

[Anonymous], PHILOS T R SOC LON B

[3]

[Anonymous], 2007, IMINOSUGARS SYNTHESI

[4] CHROMATOGRAPHIC SEPARATION OF ANOMERIC GLYCOSIDES .2. NEW CRYSTALLINE METHYLFURANOSIDES OF GALACTOSE, ARABINOSE AND XYLOSE [J].

AUGESTAD, I ;

BERNER, E .

ACTA CHEMICA SCANDINAVICA, 1954, 8 (02) :251-256

[5] New therapeutic options for lysosomal storage disorders: enzyme replacement, small molecules and gene therapy [J].

Beck, Michael .

HUMAN GENETICS, 2007, 121 (01) :1-22

[6]

Beutler E., 2001, METABOLIC MOL BASES, V3, P3635

[7] Lysosomal storage diseases: Natural history and ethical and economic aspects [J].

Beutler, Ernest .

MOLECULAR GENETICS AND METABOLISM, 2006, 88 (03) :208-215

[8] First stereocontrolled synthesis and biological evaluation of 1,6-dideoxy-L-nojirimycin [J].

Bordier, A ;

Compain, P ;

Martin, OR ;

Ikeda, K ;

Asano, N .

TETRAHEDRON-ASYMMETRY, 2003, 14 (01) :47-51

[9] Design and synthesis of iminosugar-based inhibitors of glucosylceramide synthase: the search for new therapeutic agents against Gaucher disease [J].

Boucheron, C ;

Desvergnes, V ;

Compain, P ;

Martin, OR ;

Lavi, A ;

Mackeen, M ;

Wormald, M ;

Dwek, R ;

Butters, TD .

TETRAHEDRON-ASYMMETRY, 2005, 16 (10) :1747-1756

[10] Synthesis of 4-O-glycosylated 1-deoxynojirimycin derivatives as disaccharide mimics-based inhibitors of human β-glucocerebrosidase [J].

Boucheron, Charlotte ;

Tournieux, Sylvestre ;

Compain, Philippe ;

Martin, Olivier R. ;

Ikeda, Kyoko ;

Asano, Naoki .

CARBOHYDRATE RESEARCH, 2007, 342 (12-13) :1960-1965

← 1 2 3 4 5 6 7 8 →