US 12,012,468 B2
Cyclic polypeptides for PCSK9 inhibition
Alonso Ricardo, Cambridge, MA (US); Thomas Joseph Tucker, North Wales, PA (US); Nicolas Cedric Boyer, Somerville, MA (US); Joseph R. Stringer, Somerville, MA (US); Derek M. LaPlaca, Somerville, MA (US); Angela Dawn Kerekes, Plainfield, NJ (US); Chengwei Wu, Ambler, PA (US); Sookhee Nicole Ha, Warren, NJ (US); Hyewon Youm, Berkeley Heights, NJ (US); Mark W. Embrey, Harleysville, PA (US); Elisabetta Bianchi, Rome (IT); Danila Branca, Pomezia (IT); Raffaele Ingenito, Pomezia (IT); Willy Costantini, Pomezia (IT); Alessia Santoprete, Rome (IT); Roberto Costante, Silvi (IT); Immacolata Conte, Pomezia (IT); Stefania Colarusso, Rome (IT); Eric J. Gilbert, Scotch Plains, NJ (US); Aurash Shahripour, Gaithersburg, MD (US); and Yusheng Xiong, Plainsboro, NJ (US)
Assigned to MERCK SHARP & DOHME LLC, Rahway, NJ (US); and RA PHARMACEUTICALS, INC., Cambridge, MA (US)
Filed by Merck Sharp & Dohme LLC, Rahway, NJ (US)
Filed on Sep. 27, 2022, as Appl. No. 17/935,726.
Application 17/935,726 is a division of application No. 17/253,864, granted, now 11,530,244, previously published as PCT/US2019/038250, filed on Jun. 20, 2019.
Claims priority of provisional application 62/688,058, filed on Jun. 21, 2018.
Prior Publication US 2023/0303625 A1, Sep. 28, 2023
Int. Cl. C07K 7/64 (2006.01); A61K 38/00 (2006.01)
CPC C07K 7/64 (2013.01) [A61K 38/00 (2013.01)] 15 Claims
 
1. A cyclic peptide of Formula (II):

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof;
wherein:
X is selected from the group consisting of F, OH, Br, Me, OMe, Cl, and CF3;
A1 is an acyl protected amine or is absent; or A1 is an amine that is linked by a covalent bond to amino acids selected from the group consisting of (MFF), (MFF-HIS), (MFF-HIS-NVA), and (LYS-SER-NVA), wherein MFF has the amino acid structure

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NVA has the amino acid structure

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and the terminal amine is acyl protected;
R1 is selected from the group consisting of the amino acid side chains of

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and THR;
R2 is selected from the group consisting of the amino acid side chains of

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ALA, GLY, and

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R3 is selected from the group consisting of the amino acid side chains of ALA, ASP, ASN,

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and THR;
R4 is selected from the group consisting of the amino acid side chains of

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ALA, HIS, and THR;
R5 is selected from the group consisting of the amino acid side chains of

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A2 is absent or

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wherein each amino acid residue is optionally an N-methylated amino acid;
wherein each amino acid residue can be the R or S-enantiomer configuration; and
n is 0, 1, 2, 3, or 4.