Abstract
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.
Highlights
Glucosylceramide synthase (GCS), known to catalyze glucosylceramide (GlcCer) synthesis from ceramide (Cer) and uridine diphosphate-glucose (UDP-glucose), is a key enzyme in glycolipid synthesis, as GlcCer is the starting point for the synthesis of other glycolipids.[1]
Charged Aerosol Detector (CAD) demonstrates safety liabilities such as modulation of ion channel activity, potentially increasing the risk of cardiovascular (CV) adverse effects.[22−24] Given the interest in GCS inhibitors as a therapeutic target for Gaucher’s disease (GD) and Parkinson’s disease, we explored a brain-penetrant GCS inhibitor without a basic amine that generates a cationic structure to mitigate CV risks
To identify novel compounds that decrease levels of GlcCer, we conducted a highthroughput screening campaign using a cellular assay, which measured the decrease of GlcCer in fibroblasts obtained from patients with GD
Summary
Glucosylceramide synthase (GCS), known to catalyze glucosylceramide (GlcCer) synthesis from ceramide (Cer) and uridine diphosphate-glucose (UDP-glucose), is a key enzyme in glycolipid synthesis, as GlcCer is the starting point for the synthesis of other glycolipids.[1]. The potent and metabolically stable GCS inhibitor 15 exhibited moderate brain penetration (Kpuu,brain = 0.20; see Table S1 for detailed results); 15 showed human ether-a-go-go-related gene (hERG) inhibition (51.4% inhibition at 10 μM) and poor solubility (
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