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.