Synthesis of a Complex and Highly Potent PCSK9 Inhibitor
Jeffrey T. Kuethe, Joshua E.-Y. Lee, David A. Thaisrivongs, Nobuyoshi Yasuda, Scott R. Pollack, Joseph F. Leone, Jimmy DaSilva, Mirlinda Biba, Fuh‐Rong Tsay, Erik L. Regalado, Ji Qi, Hongming Li, Guilherme Dal Poggetto, Ryan D. Cohen
Abstract
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 .