Discovery of Brain-Penetrant Glucosylceramide Synthase Inhibitors with a Novel Pharmacophore

Inhibition of glucosylceramide
synthase (GCS) is a major therapeutic
strategy for Gaucher’s disease and has been suggested as a
potential target for treating Parkinson’s disease. Herein,
we report the discovery of novel brain-penetrant GCS inhibitors. Assessment
of the structure–activity relationship revealed a unique pharmacophore
in this series. The lipophilic ortho-substituent of aromatic ring
A and the appropriate directionality of aromatic ring B were key for
potency. Optimization of the absorption, distribution, metabolism,
elimination, toxicity (ADMETox) profile resulted in the discovery
of T-036, a potent GCS inhibitor in vivo. Pharmacophore-based
scaffold hopping was performed to mitigate safety concerns associated
with T-036. The ring opening of T-036 resulted
in another potent GCS inhibitor with a lower toxicological risk, T-690, which reduced glucosylceramide in a dose-dependent
manner in the plasma and cortex of mice. Finally, we discuss the structural
aspects of the compounds that impart a unique inhibition mode and
lower the cardiovascular risk.