Development of Adamantan-1-yl-methoxy-Functionalized 1-Deoxynojirimycin Derivatives as Selective Inhibitors of Glucosylceramide Metabolism in Man

Abstract

In this article, we present a straightforward synthesis of adamantan-1-yl-methoxy-functionalized 1-deoxynojirimycin derivatives. The used synthetic routes are flexible and can be used to create a wide variety of lipophilic mono- and difunctionalized 1-deoxynojirimycin derivatives. The compounds reported here are lipophilic iminosugar based on lead compound 4, a potent inhibitor of the three enzymes involved in the metabolism of the glycosphingolipid glucosylceramide. Iminosugar-based inhibitors of glucosylceramide synthase, one of these three enzymes, have attracted increasing interest over the past decade due to the crucial role of this enzyme in glycosphingolipid biosynthesis. Combined with the fact that an increasing number of pathological processes are being linked to excessive glycosphingolipid levels, glucosylceramide synthase becomes a very attractive therapeutic and research target. Our results presented here demonstrate that relocating the lipophilic moiety from the nitrogen atom to other positions on the 1-deoxynojirimycin ring system does not lead to a more potent or selective inhibitor of glucosylceramide synthase. The beta-aza-C-glycoside analogue (17) retained the best inhibitory potency for glucosylceramide synthase and is a more potent inhibitor than the therapeutic agent N-butyl-1-deoxynojirimycin (3), marketed as treatment for Gaucher disease under the commercial name Zavesca.

β-Glucosidase 2 (GBA2) Activity and Imino Sugar Pharmacology

“…The enzymes catalyzing the biosynthesis and lysosomal hydrolysis of GlcCer, UGCG, and GBA, respectively, are the subjects of multiple medicinal chemistry studies employing alkylated derivatives of the imino sugar deoxynojirimycin, deoxygalactonojirimycin (23)(24)(25)(26), and related compounds (27)(28)(29). Inhibition of UGCG using alkylated imino sugars is the FIGURE 1.…”

The Glucosylceramide Synthase InhibitorN-(5-Adamantane-1-yl-methoxy-pentyl)-deoxynojirimycin Induces Sterol Regulatory Element-Binding Protein-Regulated Gene Expression and Cholesterol Synthesis in HepG2 Cells

“…We have described previously that N-(5-adamantane-1-ylmethoxy-pentyl)-deoxynojirimycin (AMP-DNM), an inhibitor of glucosylceramide synthase, specifically lowers glycosphingolipid levels without affecting ceramide levels in various cell models (Overkleeft et al, 1998;Aerts et al, 2003;Wennekes et al, 2007). AMP-DNM was found to reverse insulin resistance and normalize blood glucose levels in animal models of diabetes and obesity (Zucker fa/fa rats, diet-induced obese mice, and ob/ob mice).…”

The development and use of small molecule inhibitors of glycosphingolipid metabolism for lysosomal storage diseases

“…Miglustat cocrystallizes with lysosomal glucocerebrosidase and its binding is greater at neutral compared with acidic pH ( 40 ). The adamantyl analog of miglustat, N-(5-adamantane-1-yl-methoxypentyl) deoxynojirimycin, is signifi cantly more active as a glucosylceramide synthase inhibitor (IC 50 150 nM) and retains the ability to penetrate the blood-brain barrier ( 41 ). However, when the adamantyl compound and miglustat were studied in CNSbased models of glycosphingolipidoses, brain glucosylceramide levels increased markedly ( 42 ).…”