PK/PD Disconnect Observed with a Reversible Endothelial Lipase Inhibitor

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Pharmacology

Background:

• Endothelial lipase (EL) plays a role in HDL metabolism.
• Developing selective EL inhibitors is a therapeutic strategy for dyslipidemia.
• Existing assays may not fully predict in vivo efficacy.

Purpose of the Study:

• To identify and optimize reversible inhibitors of endothelial lipase (EL).
• To evaluate the in vivo efficacy of a novel EL inhibitor in raising HDL-cholesterol.
• To assess the translatability of in vitro enzyme inhibition data to in vivo outcomes.

Main Methods:

• Screening of chemical libraries for EL inhibitory activity.
• Structure-activity relationship studies and chemical optimization.
• In vitro enzyme inhibition assays (EL, LPL, HL) and pharmacokinetic profiling.
• In vivo studies in animal models to assess HDL-cholesterol levels.

Main Results:

• Identified potent reversible EL inhibitors, including compounds 5 and 6a.
• Optimized compound 6a into 7c with improved pharmacokinetics.
• Compound 7c demonstrated selective EL inhibition but did not increase HDL-C in vivo.
• Achieved targeted plasma exposures for 7c based on in vitro data.

Conclusions:

• Novel reversible EL inhibitors were synthesized and characterized.
• The developed tool molecule (7c) did not increase HDL-C in vivo.
• Current in vitro assays may not adequately predict in vivo efficacy for EL inhibitors.
• Development of more physiologically relevant assays is crucial for guiding drug discovery.