N-Methyl-N-Alkylaminocyclopentanes: Powerful and Selective -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 beta-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 beta-d-glucocerebrosidase. However, none of these compounds exhibit significant activity enhancement of Morbus Gaucher related p.N409S/p.L483P mutant beta-d-glucocerebrosidase.