Fluorinated Isoindolinone-Based Glucosylceramide Synthase Inhibitors with Low Human Dose Projections

Area of Science:

• Medicinal Chemistry
• Neuroscience
• Pharmacology

Background:

• Parkinson's Disease (PD) may involve glycosphingolipid accumulation and lysosomal dysfunction.
• Inhibition of glucosylceramide synthase (GCS) is a potential therapeutic strategy for PD.
• Existing GCS inhibitors require optimization for oral bioavailability, CNS penetration, and safety profiles.

Purpose of the Study:

• To optimize an orally bioavailable and CNS-penetrant isoindolinone class of GCS inhibitors.
• To identify a compound with a lower projected human dose, minimal P-glycoprotein (P-gp) efflux, and an acceptable pregnane X receptor (PXR) profile.
• To discover a novel GCS inhibitor for potential Parkinson's Disease treatment.

Main Methods:

• Late-stage optimization of lead compound 1 within the isoindolinone class.
• Strategic fluorine substitution to modulate pharmacokinetic and pharmacodynamic properties.
• Application of predicted volume ligand efficiency and minimized electrostatic potentials (V_min) for compound selection and P-gp structure-activity relationship (SAR) rationalization.

Main Results:

• Successful identification of compound 12, a GCS inhibitor with improved properties.
• Achieved alignment of a lower human dose projection with reduced P-gp efflux.
• Demonstrated favorable PXR selectivity for compound 12.

Conclusions:

• Fluorine substitution is an effective strategy for optimizing GCS inhibitors.
• Compound 12 represents a promising therapeutic candidate for Parkinson's Disease.
• The applied computational strategies facilitated the discovery of a drug with improved efficacy and safety profiles.