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.

Automated summary

This study reports the discovery of novel brain-penetrant GCS inhibitors, which have the potential to treat Gaucher's disease and Parkinson's disease. The optimization of the structure and ADMETox profile resulted in the identification of T-036 as a potent GCS inhibitor in vivo. Scaffold hopping led to the development of another GCS inhibitor, T-690, with lower toxicological risk. The structural aspects of the compounds were discussed in terms of their unique inhibition mode and reduced cardiovascular risk.