Metachromatic leukodystrophy (MLD) is a rare, genetic lysosomal storage disorder caused by the deficiency of
arylsulfatase A enzyme, which results in the accumulation of
sulfatide in the lysosomes of the tissues of central and peripheral nervous systems, leading to progressive
demyelination and neurodegeneration. Currently there is no cure for this disease, and the only approved
therapy, hematopoietic stem cell transplant, has limitations. We proposed substrate reduction
therapy (SRT) as a novel approach to treat this disease, by inhibiting
ceramide galactosyltransferase enzyme (UGT8). This resulted in the identification of a
thienopyridine scaffold as a starting point to initiate medicinal chemistry. Further optimization of hit compound 1 resulted in the identification of brain penetrable, orally bioavailable compound 19, which showed efficacy in the in vivo pharmacodynamic models, indicating the potential to treat MLD with UGT8 inhibitors.