Synthesis of a Complex and Highly Potent PCSK9 Inhibitor.

Autor:	Kuethe JT; Department of Process Research and Development, Merck & Co., Inc., Rahway, New Jersey 07065, United States., Lee J; Department of Process Research and Development, Merck & Co., Inc., Rahway, New Jersey 07065, United States., Thaisrivongs D; Department of Process Research and Development, Merck & Co., Inc., Rahway, New Jersey 07065, United States., Yasuda N; Department of Process Research and Development, Merck & Co., Inc., Rahway, New Jersey 07065, United States., Pollack SR; Department of Process Research and Development, Merck & Co., Inc., Rahway, New Jersey 07065, United States., Leone J; Department of Process Research and Development, Merck & Co., Inc., Rahway, New Jersey 07065, United States., DaSilva J; Department of Process Research and Development, Merck & Co., Inc., Rahway, New Jersey 07065, United States., Biba M; Department of Process Research and Development, Merck & Co., Inc., Rahway, New Jersey 07065, United States., Tsay FR; Department of Process Research and Development, Merck & Co., Inc., Rahway, New Jersey 07065, United States., Regalado EL; Department of Process Research and Development, Merck & Co., Inc., Rahway, New Jersey 07065, United States., Qi J; Department of Process Research and Development, Merck & Co., Inc., Rahway, New Jersey 07065, United States., Li H; Department of Process Research and Development, Merck & Co., Inc., Rahway, New Jersey 07065, United States., Poggetto GD; Department of Process Research and Development, Merck & Co., Inc., Rahway, New Jersey 07065, United States., Cohen R; Department of Process Research and Development, Merck & Co., Inc., Rahway, New Jersey 07065, United States.
Jazyk:	angličtina
Zdroj:	Organic letters [Org Lett] 2023 Jul 14; Vol. 25 (27), pp. 5001-5005. Date of Electronic Publication: 2023 Jun 29.
DOI:	10.1021/acs.orglett.3c01635
Abstrakt:	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 .
Databáze:	MEDLINE
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