Patrick Weber, Roland Fischer, Seyed A. Nasseri, Bettina M. Pabst, Herwig Prasch, Arnold E. Stütz, Martin Thonhofer, Stephen G. Withers, Werner Windischhofer, Tanja M. Wrodnigg
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N-Methyl-N-Alkylaminocyclopentanes: Powerful and Selective β-d-Glucocerebrosidase Inhibitors
Building upon a previously established (2+3)-cycloaddition strategy, a series of N,N-dialkylated aminocyclopentanes was synthesized using a partially protected eno-furanose as the starting point. The resulting N-methylisoxazolidine was subsequently transformed into the corresponding aminocyclopentane, which was further N-alkylated, yielding a collection of compounds with potential as inhibitors and pharmacological chaperones of β-d-glucocerebrosidase. A comprehensive screening involving a range of biologically relevant glycosidases unveiled that these compounds exhibit remarkable potency and selectivity as inhibitors of human lysosomal β-d-glucocerebrosidase. However, none of these compounds exhibit significant activity enhancement of Morbus Gaucher related p.N409S/p.L483P mutant β-d-glucocerebrosidase.
期刊介绍:
Helvetica Chimica Acta, founded by the Swiss Chemical Society in 1917, is a monthly multidisciplinary journal dedicated to the dissemination of knowledge in all disciplines of chemistry (organic, inorganic, physical, technical, theoretical and analytical chemistry) as well as research at the interface with other sciences, where molecular aspects are key to the findings. Helvetica Chimica Acta is committed to the publication of original, high quality papers at the frontier of scientific research. All contributions will be peer reviewed with the highest possible standards and published within 3 months of receipt, with no restriction on the length of the papers and in full color.