Cyclic polypeptides for PCSK9 inhibition

Patent metadata

Field	Value
Publication number	US-12012468-B2
Application number	US-202217935726-A
Country	US
Kind code	B2
Filing date	Sep 27, 2022
Priority date	Jun 21, 2018
Publication date	Jun 18, 2024
Grant date	Jun 18, 2024

Abstract

Provided herein are cyclic polypeptide compounds that can, e.g., bind specifically to human proprotein convertase subtilisin/kexin type 9 (PCSK9) and optionally also inhibit interaction between human PCSK9 and human low density lipoprotein receptor (LDLR), and pharmaceutical compositions comprising one or more of these compounds. Also provided are methods of reducing LDL cholesterol level in a subject in need thereof that include administering to the subject one or more of the cyclic polypeptide compounds or a pharmaceutical composition provided herein.

First claim

What is claimed is:

1. A cyclic peptide of Formula (II):

or a pharmaceutically acceptable salt thereof;

wherein:
X is selected from the group consisting of F, OH, Br, Me, OMe, Cl, and CF 3 ;
A 1 is an acyl protected amine or is absent; or A 1 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

NVA has the amino acid structure

and the terminal amine is acyl protected;
R 1 is selected from the group consisting of the amino acid side chains of

and THR;
R 2 is selected from the group consisting of the amino acid side chains of

ALA, GLY, and

R 3 is selected from the group consisting of the amino acid side chains of ALA, ASP, ASN,

and THR;
R 4 is selected from the group consisting of the amino acid side chains of

ALA, HIS, and THR;
R 5 is selected from the group consisting of the amino acid side chains of

A 2 is absent or

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.

2. The cyclic peptide of claim 1 , wherein the cyclic peptide is selected from the group consisting of:

011

012

020

021

022

023

031

143

144

145

146

147

148

149

155

156

157

159

162

Assignees

• Merck Sharp & Dohme Llc
• Ra Pharmaceuticals Inc

Inventors

• Ricardo Alonso
• Tucker Thomas Joseph
• Boyer Nicolas Cedric
• Stringer Joseph R
• Laplaca Derek M
• Kerekes Angela Dawn
• Wu Chengwei
• Ha Sookhee Nicole
• Youm Hyewon
• Embrey Mark W
• Bianchi Elisabetta
• Branca Danila
• Ingenito Raffaele
• Costantini Willy
• Santoprete Alessia
• Costante Roberto
• Conte Immacolata
• Colarusso Stefania
• Gilbert Eric J
• Shahripour Aurash
• Xiong Yusheng

Classifications

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• C07K7/64 Primary

  Cyclic peptides containing only normal peptide links · CPC title

• C07K7/06 Primary

  having 5 to 11 amino acids · CPC title