Discovery and Optimization of Selective Brain-Penetrant EBP Inhibitors that Enhance Oligodendrocyte Formation

Area of Science:

• Medicinal Chemistry
• Neuroscience
• Drug Discovery

Background:

• Emopamil binding protein (EBP) is a key enzyme in cholesterol biosynthesis.
• Inhibiting EBP can promote oligodendrocyte formation, a potential therapeutic strategy for multiple sclerosis (MS).

Purpose of the Study:

• To discover and optimize novel, brain-penetrant, orally bioavailable EBP inhibitors.
• To validate EBP inhibition as a therapeutic approach for MS.

Main Methods:

• Structure-based drug design utilizing a known literature compound.
• Optimization of a hydantoin-based scaffold for potency, physicochemical properties, and safety.
• In vivo studies in rodents to assess pharmacokinetics and brain penetration.
• In vitro studies using human cortical organoids.

Main Results:

• Identified a novel hydantoin-based scaffold with balanced properties and improved in vitro safety.
• Developed EBP inhibitor 11 with enhanced metabolic turnover, potency, and brain penetration.
• Demonstrated in vivo target engagement via zymostenol accumulation in the brain.
• Showcased compound 11's ability to enhance oligodendrocyte formation in human cortical organoids.

Conclusions:

• EBP inhibition is a viable therapeutic strategy for promoting oligodendrocyte formation.
• Compound 11 represents a promising drug candidate for MS treatment due to its brain penetrance and efficacy.
• Further development of EBP inhibitors could lead to novel therapies for demyelinating diseases like MS.