4-[4-(4-methylphenyl)sulfonyl-1-piperazinyl]-2-thiophen-2-ylquinazoline and Gaucher-Disease

Gaucher disease is a lysosomal storage disorder (LSD) caused by deficiency in the enzyme glucocerebrosidase (GC). Small molecule chaperones of protein folding and translocation have been proposed as a promising therapeutic approach to this LSD. Most small molecule chaperones described in the literature contain an iminosugar scaffold. Here we present the discovery and evaluation of a new series of GC inhibitors with a quinazoline core. We demonstrate that this series can improve the translocation of GC to the lysosome in patient-derived cells. To optimize this chemical series, systematic synthetic modifications were performed and the SAR was evaluated and compared using three different readouts of compound activity: enzymatic inhibition, enzyme thermostabilization, and lysosomal translocation of GC.

Topics: Cell Line; Fibroblasts; Gaucher Disease; Glucosylceramidase; Humans; Hymecromone; Immunohistochemistry; Lysosomes; Magnetic Resonance Spectroscopy; Microscopy, Confocal; Molecular Chaperones; Quinazolines; Spectrometry, Mass, Electrospray Ionization; Spleen; Structure-Activity Relationship