Cyclic polypeptides for PCSK9 inhibition

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

Assignees

Merck Sharp & Dohme LLC • UCB Inc

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.

Core Innovation

The invention relates to a cyclic peptide of Formula (II), or a pharmaceutically acceptable salt thereof, with structural variability controlled by selected substituents and residue selections. X is selected from F, OH, Br, Me, OMe, Cl, and CF3, and the framework further specifies optional structural elements through A1 and A2 presence or absence, with covalent linkage of A1 to amino acids selected from (MFF), (MFF-HIS), (MFF-HIS-NVA), and (LYS-SER-NVA).

The Formula (II) cyclic peptide includes variable side-chain selections R1 through R5, with R1, R2, R3, and R4 selected from enumerated amino acid side chains including THR, ALA, GLY, ASP, ASN, and HIS, and R5 selected from the claim-defined side-chain options. Each amino acid residue is optionally an N-methylated amino acid, each amino acid residue can be the R or S-enantiomer configuration, and n is 0, 1, 2, 3, or 4.

The cyclic peptide compounds are designed to bind human PCSK9 and optionally inhibit PCSK9-LDLR (EGF-A domain) interaction. The disclosure also associates the compounds with pharmaceutical compositions and therapeutic methods aimed at reducing LDL cholesterol, including treating or preventing hypercholesterolemia and comorbid diseases such as nephrotic syndrome, kidney failure, coronary artery disease, atherosclerosis, stroke, peripheral vascular disease, diabetes, and high blood pressure.

Claims Coverage

The independent claim covers a cyclic peptide of Formula (II) with defined substituent, residue-variable side-chain, attachment/presence rules, optional N-methylation, optional R/S configuration, and n from 0 to 4, including pharmaceutically acceptable salts. Dependent coverage extends to four therapeutic and mechanistic features: inhibiting PCSK9 activity in a subject, inhibiting PCSK9 and the EGF-A domain of LDLR interaction, inhibiting PCSK9 activity in a cell by contacting the cell, and reducing LDL cholesterol levels in a subject.

Overall, the claim coverage centers on a Formula (II) cyclic peptide with constrained substituent and residue-variable options, optional A1 linkage/acyl protection, optional N-methylation, R/S stereochemical flexibility, and n from 0 to 4. Dependent claims apply the cyclic peptide to inhibiting PCSK9 activity, inhibiting PCSK9-LDLR interaction, inhibiting PCSK9 activity in a cell, and reducing LDL cholesterol levels, with one claim further limited by comorbid disease selection.

Stated Advantages

Documented Applications