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 1 is presented. Construction of Northern fragment 2, followed by stepwise installation of Eastern 3, Southern 4, and Western 5 fragments, provided macrocyclic precursor 19. This intermediate was cross-linked via an intramolecular azide-alkyne click reaction, which preceded macrolactamization to afford the core framework of compound 1. Finally, coupling with poly(ethylene glycol) side-chain-based 6 gave the PCSK9 inhibitor 1.

Citation

Jeffrey T Kuethe, Joshua Lee, David Thaisrivongs, Nobuyoshi Yasuda, Scott R Pollack, Joseph Leone, Jimmy DaSilva, Mirlinda Biba, Fuh-Rong Tsay, Erik L Regalado, Ji Qi, Hongming Li, Guilherme Dal Poggetto, Ryan Cohen. Synthesis of a Complex and Highly Potent PCSK9 Inhibitor. Organic letters. 2023 Jul 14;25(27):5001-5005

Mesh Tags

Substances

PMID: 37382389

search → result