Efficient Synthesis of Enlicitide Chloride through Convergent Solution-Phase and Hybrid Solution-Solid-Phase...

Area of Science:

• Medicinal Chemistry
• Cardiovascular Pharmacology
• Synthetic Organic Chemistry

Background:

• Elevated low-density lipoprotein cholesterol (LDL-C) is a major risk factor for atherosclerotic cardiovascular disease (ASCVD).
• The interaction between proprotein convertase subtilisin/kexin-type 9 (PCSK9) and low-density lipoprotein receptors (LDLR) plays a key role in LDL-C regulation.
• PCSK9 inhibitors represent a promising therapeutic strategy for managing hyperlipidemia and reducing ASCVD risk.

Purpose of the Study:

• To report efficient and robust synthetic strategies for the total synthesis of enlicitide, a novel PCSK9 inhibitor.
• To explore the potential of enlicitide as an orally administered peptide therapeutic for ASCVD.
• To establish a foundation for medicinal chemistry studies and structural diversification of enlicitide.

Main Methods:

• Development of a fully solution-phase synthetic strategy for enlicitide.
• Implementation of a hybrid solution-solid-phase strategy combining Fmoc-based solid-phase peptide synthesis (SPPS) and solution-phase ring-closing reactions.
• Validation of synthetic routes for efficient and time-effective preparation of enlicitide.

Main Results:

• Two distinct, efficient, and robust preparation processes for the total synthesis of enlicitide were successfully established.
• The hybrid strategy, utilizing Fmoc-SPPS and solution-phase cyclization, proved particularly time-effective.
• The developed methods enable scalable production and facilitate further structural modifications of enlicitide.

Conclusions:

• The successful total synthesis of enlicitide provides a viable route for its production and further investigation.
• The established synthetic methodologies pave the way for developing orally administered peptide therapeutics targeting PCSK9.
• Enlicitide's unique structure and potent hypolipidemic potential position it as a promising candidate for ASCVD treatment and drug development.