Synthesis of a Complex and Highly Potent PCSK9 Inhibitor.

The solution-based gram-scale synthesis of complex and highly potent proprotein convertase subtilisin-like/kexin type 9 (PCSK9) inhibitor is presented. Construction of Northern fragment , followed by stepwise installation of Eastern , Southern , and Western fragments, provided macrocyclic precursor . This intermediate was cross-linked via an intramolecular azide-alkyne click reaction, which preceded macrolactamization to afford the core framework of compound . Finally, coupling with poly(ethylene glycol) side-chain-based gave the PCSK9 inhibitor .