C-Branched Iminosugars as Selective Pharmacological Chaperones of Lysosomal α-Glucosidase for the Treatment of Pompe Disease.

We report herein the design and synthesis of a series of 5-C-alkyldeoxynojirimycins from l-sorbose, through an efficient and scalable method amenable to preparing a large variety of analogues. The interaction of this class of compounds with human acid α-glucosidase (GAA), the genetically defective enzyme in patients suffering from Pompe disease, was investigated to identify pharmacological chaperones exhibiting high selectivity for this enzyme. Crystallographic analyses provided a rationale for their binding mode to GAA and chaperone activity. The effects of 5-C-phenethyl-DNJ (4c) were evaluated on GAA activity enhancement in cells from Pompe disease patients and in vivo in GAA-KO mice. The significant increase of GAA activity in the presence of 4c in various tissues, particularly in the diaphragm, encourages further studies on this class of small molecules toward developing clinical drugs. Their chaperone activity and excellent selectivity may offer potential benefits over the current treatments for Pompe disease.