Discovery of potent, nonsystemic apical sodium-codependent bile acid transporter inhibitors (Part 1)

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Biochemistry

Background:

• Elevated low-density lipoprotein (LDL) cholesterol is a primary risk factor for atherosclerosis and coronary artery disease (CAD).
• Current treatments may have systemic side effects; novel approaches targeting bile acid reabsorption are needed.

Purpose of the Study:

• To synthesize and evaluate novel benzothiepine derivatives as inhibitors of the apical sodium-dependent bile acid transporter (ASBT).
• To develop a locally acting ASBT inhibitor for lowering serum cholesterol with reduced systemic exposure.

Main Methods:

• Synthesis of novel benzothiepine derivatives (2,3,4,5-tetrahydro-5-aryl-1-benzothiepin-4-ol 1,1-dioxides).
• Inhibition assays measuring apical sodium-dependent bile acid transport (ASBT)-mediated uptake of [(14)C]taurocholate in H14 cells.
• Structure-activity relationship (SAR) studies involving substituent modifications.

Main Results:

• A specific stereoisomer (3R,4R,5R/3S,4S,5S racemate) demonstrated superior potency.
• Electron-donating groups (e.g., dimethylamino) and quaternary ammonium substituents enhanced potency and reduced systemic exposure.
• Achieved a 6000-fold improvement in ASBT inhibition with a locally acting drug candidate.

Conclusions:

• Benzothiepine derivatives are effective ASBT inhibitors with potential for treating hypercholesterolemia.
• Optimized compounds show high potency and minimal systemic exposure, suitable for local action.
• This class of compounds represents a promising therapeutic strategy for managing CAD risk factors.