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

Boucheron, Charlotte; Desvergnes, Valérie; Compain, Philippe; Martin, Olivier R.; Lavi, Alan; Mackeen, Muhammad Mukram Mohamed; Wormald, Mark R.; Dwek, Raymond A.; Butters, Terry D.

doi:10.1016/j.tetasy.2005.03.015

Cited by 46 publications

(39 citation statements)

References 17 publications

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“…[29][30][31][32] As expected, deprotection of the amine (giving 7), followed by a base-mediated Michael addition, produced a pair of stereoisomers of 2 0 -ketonyl iminosugar. Then the 4-OH was protected by Ac 2 O/Py to afford 8 (see Table 1).…”

Section: Resultssupporting

confidence: 69%

Synthesis of N-substituted iminosugars from 2′-carbonyl-C-glycofuranosides

Luo

Zou

Shao

2009

Carbohydrate Research

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Section: Resultssupporting

confidence: 69%

Synthesis of N-substituted iminosugars from 2′-carbonyl-C-glycofuranosides

Luo

Zou

Shao

2009

Carbohydrate Research

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“…A similar trend is seen in the L-ido-configured series. Again, GCS inhibitory potency increases with increasing N-alkyl substituent, and again, the N-alkyloxyalkyl derivatives (22)(23)(24)(25)(26)(27) outperform the N-alkyl species (10)(11)(12)(13)(14)(15). Head-to-head comparison of two stereoisomers from the two series reveals that in general the L-ido congener is the most potent GCS inhibitor.…”

mentioning

confidence: 90%

Identification of Potent and Selective Glucosylceramide Synthase Inhibitors from a Library of N-Alkylated Iminosugars

Ghisaidoobe

Bikker

Bruijn

et al. 2010

ACS Med. Chem. Lett.

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Glucosylceramide synthase (GCS) is an important target for clinical drug development for the treatment of lysosomal storage disorders and a promising target for combating type 2 diabetes. Iminosugars are useful leads for the development of GCS inhibitors; however, the effective iminosugar type GCS inhibitors reported have some unwanted cross-reactivity toward other glyco-processing enzymes. In particular, iminosugar type GCS inhibitors often also inhibit to some extent human acid glucosylceramidase (GBA1) and the nonlysosomal glucosylceramidase (GBA2), the two enzymes known to process glucosylceramide. Of these, GBA1 itself is a potential drug target for the treatment of the lysosomal storage disorder, Gaucher disease, and selective GBA1 inhibitors are sought after as potential chemical chaperones. The physiological importance of GBA2 in glucosylceramide processing in relation to disease states is less clear, and here, selective inhibitors can be of use as chemical knockout entities. In this communication, we report our identification of a highly potent and selective N-alkylated L-ido-configured iminosugar. In particular, the selectivity of 27 for GCS over GBA1 is striking.

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“…However, a recent study by Compain, Martin, and co-workers on di-or trialkylated derivatives 41-44 showed this did not result in more potent GCS inhibitors (Figure 7). [209] Several pyrrolidine iminosugars have also proven to be GCS inhibitors. In 2000, Butters et al revealed DMDP derivative 47 as a GCS inhibitor of comparable activity as 4 ( Figure 8).…”

Section: Inhibitors Of Glucosylceramide Synthasementioning

confidence: 99%

Glycosphingolipids—Nature, Function, and Pharmacological Modulation

et al. 2009

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The discovery of the glycosphingolipids is generally attributed to Johan L. W. Thudichum, who in 1884 published on the chemical composition of the brain. In his studies he isolated several compounds from ethanolic brain extracts which he coined cerebrosides. He subjected one of these, phrenosin (now known as galactosylceramide), to acid hydrolysis, and this produced three distinct components. One he identified as a fatty acid and another proved to be an isomer of D-glucose, which is now known as D-galactose. The third component, with an "alkaloidal nature", presented "many enigmas" to Thudichum, and therefore he named it sphingosine, after the mythological riddle of the Sphinx. Today, sphingolipids and their glycosidated derivatives are the subjects of intense study aimed at elucidating their role in the structural integrity of the cell membrane, their participation in recognition and signaling events, and in particular their involvement in pathological processes that are at the basis of human disease (for example, sphingolipidoses and diabetes type 2). This Review details some of the recent findings on the biosynthesis, function, and degradation of glycosphingolipids in man, with a focus on the glycosphingolipid glucosylceramide. Special attention is paid to the clinical relevance of compounds directed at interfering with the factors responsible for glycosphingolipid metabolism.

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

Cited by 46 publications

References 17 publications

Synthesis of N-substituted iminosugars from 2′-carbonyl-C-glycofuranosides

Synthesis of N-substituted iminosugars from 2′-carbonyl-C-glycofuranosides

Identification of Potent and Selective Glucosylceramide Synthase Inhibitors from a Library of N-Alkylated Iminosugars

Glycosphingolipids—Nature, Function, and Pharmacological Modulation

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