Cyclic polypeptides for PCSK9 inhibition

Patent metadata

Field	Value
Publication number	US-11530244-B2
Application number	US-201917253864-A
Country	US
Kind code	B2
Filing date	Jun 20, 2019
Priority date	Jun 21, 2018
Publication date	Dec 20, 2022
Grant date	Dec 20, 2022

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 polycyclic peptide of Formula (I):

or a pharmaceutically acceptable salt thereof;

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

R 1 is selected from the group consisting of the amino acid side chains of

and TYR;
R 2 is selected from the group consisting of the amino acid side chains of ALA,

THR, and VAL;
R 3 is selected from the group consisting of the amino acid side chains of ALA, ASP,

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

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

L 1 is

A 2 is absent or

P 1 is selected from the group consisting of H, acetyl,

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 polycyclic peptide of claim 1 , wherein the polycyclic peptide is selected from:

002

003

004

005

006

007

008

009

010

013

014

016

017

018

019

024

025

026

027

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

• 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

• 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

• C07K7/06 Primary

  having 5 to 11 amino acids · CPC title