N‐Methyl‐N‐Alkylaminocyclopentanes: Powerful and Selective β‐d‐Glucocerebrosidase Inhibitors

Abstract

AbstractBuilding 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.