Synthesis of a Complex and Highly Potent PCSK9 Inhibitor

  • Org Lett. 2023 Jul 14;25(27):5001-5005. doi: 10.1021/acs.orglett.3c01635.
Jeffrey T Kuethe  1 ,  Joshua Lee  1 ,  David Thaisrivongs  1 ,  Nobuyoshi Yasuda  1 ,  Scott R Pollack  1 ,  Joseph Leone  1 ,  Jimmy DaSilva  1 ,  Mirlinda Biba  1 ,  Fuh-Rong Tsay  1 ,  Erik L Regalado  1 ,  Ji Qi  1 ,  Hongming Li  1 ,  Guilherme Dal Poggetto  1 ,  Ryan Cohen  1
Affiliations
  • 1. Department of Process Research and Development, Merck & Co., Inc., Rahway, New Jersey 07065, United States.
PMID: 37382389 DOI: 10.1021/acs.orglett.3c01635
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.

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