Concise asymmetric synthesis of new enantiomeric<i>C</i>-alkyl pyrrolidines acting as pharmacological chaperones against Gaucher disease
Tessa Castellan, Virginie Garcia, Frédéric Rodriguez, Isabelle Fabing, Yevhenii Shchukin, My Lan Tran, Stéphanie Ballereau, Thierry Levade, Yves Génisson, Cécile Baudoin‐Dehoux
Abstract
A concise and asymmetric synthesis of the enantiomeric pyrrolidines 2 and ent-2 are herein reported. Both enantiomers were assessed as β-GCase inhibitors. While compound ent-2 acted as a poor competitive inhibitor, its enantiomer 2 proved 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 β-GCase residual activity in N370S homozygous Gaucher fibroblasts. Notably, the non-competitive inhibitor 2 displayed 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.