Concise asymmetric synthesis of new enantiomeric C-alkyl pyrrolidines acting as pharmacological chaperones against Gaucher disease

A concise and asymmetric synthesis of the enantiomeric pyrrolidines2andent-2are herein reported. Both enantiomers were assessed as beta-GCase inhibitors. While compoundent-2acted as a poor competitive inhibitor, its enantiomer2proved to be a potent non-competitive inhibitor. Docking studies were carried out to substantiate their respective protein binding mode. Both pyrrolidines were also able to enhance lysosomal beta-GCase residual activity in N370S homozygous Gaucher fibroblasts. Notably, the non-competitive inhibitor2displayed an enzyme activity enhancement comparable to that of reference compounds IFG and NN-DNJ. This work highlights the impact of inhibitors chirality on their protein binding mode and shows that, beyond competitive inhibitors, the study of non-competitive ones can lead to the identification of new relevant parmacological chaperones.