Total Synthesis of Enlicitide Decanoate

Area of Science:

• Medicinal Chemistry
• Cardiovascular Medicine
• Process Chemistry

Background:

• Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of mortality worldwide.
• Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors represent a promising therapeutic strategy for managing hyperlipidemia and reducing cardiovascular risk.
• Enlicitide decanoate is an orally bioavailable PCSK9 inhibitor under development for ASCVD treatment.

Purpose of the Study:

• To report the total synthesis of enlicitide decanoate.
• To describe the development of a manufacturing process for large-scale enlicitide production.

Main Methods:

• Convergent synthesis strategy.
• Development of a robust and efficient manufacturing process.
• Characterization of the synthesized enlicitide decanoate.

Main Results:

• Successful total synthesis of enlicitide decanoate.
• Establishment of a scalable manufacturing process.
• Enlicitide decanoate is a complex macrocyclic peptide with nonpeptide structural elements.

Conclusions:

• The developed synthetic and manufacturing process enables large-scale production of enlicitide decanoate.
• This work facilitates the clinical development of enlicitide decanoate for atherosclerotic cardiovascular disease.