Brain Penetrable Inhibitors of Ceramide Galactosyltransferase for the Treatment of Lysosomal Storage Disorders

Abstract

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.

Figure 1

Biosynthetic pathway of sulfatide formation.

Figure 2

Thienopyridine piperazines as UGT8 inhibitors.

Figure 3

(A) Efficacy and exposure of compound 19 in an acute one-day kidney PD study in adult C57Bl/6 mice. (B) Efficacy and exposure of compound 19 in a three-day brain PD study in juvenile mice.

Scheme 1. Synthesis of Compound 19

Reagents and conditions, yield: (a) 130 °C, 74%; (b) POCl₃, 85%; (c) Methylamine in methanol, 73%; (d) N-methylpyrrolidinone, diisopropyl ethylamine, 135 °C, 90%; (e) CDI, DCM, 100%; (f) SelectFluor, silver trifluoromethanesulfonate, KF, ethyl acetate, trifluoromethyltrimethylsilane, 2-fluoropyridine, 32%; (g) hydrogen chloride, ethyl acetate, 74%; (h) N-hydroxy succinimide, triethylamine, acetonitrile, 50 °C, 67%.