Cyclic polypeptides for PCSK9 inhibition
Inventors
Ricardo, Alonso • Boyer, Nicolas Cedric • Stringer, Joseph R. • LaPlaca, Derek M. • Dhamnaskar, Ketki Ashok • Ma, Zhong • Blain, Jonathan C. • Vyasamneni, Rohit
Assignees
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Publication Number
US-11814444-B2
Publication Date
2023-11-14
Expiration Date
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 cyclic peptide and bicyclic polypeptide compounds defined by Formula (I), Formula (II), and Formula (III), including pharmaceutically acceptable salts. The structures include specified amino-acid residue selections, acyl or sulfonyl protected amino acid components or an acyl protected amine, optional N-methylation, and R or S configuration at each residue, and include racemic, optically active, regio- and stereoisomeric forms, including tautomers.
The disclosed embodiments also include selection-from-group cyclic peptide options, specific figure-associated structures, and bicyclic polypeptide compounds identified by number. The scope further includes isotopically labelled compounds, including deuterium, and labeled variants, as well as fluorescent forms and labelled reagents that support detection in assay formats.
In biological context, the compounds are described as binding human PCSK9 and inhibiting the PCSK9–LDLR EGF-A interaction. The compounds are positioned for inhibition of PCSK9 activity and for reducing LDL cholesterol in subjects, including treatment and/or prevention of hypercholesterolemia and related comorbidity diseases.
Claims Coverage
The consolidated claim coverage identifies five inventive features across the independent claims: cyclic peptides of Formula (I), Formula (II), and Formula (III), a selection-from-group cyclic peptide embodiment, and a separately enumerated bicyclic polypeptide compound set. The structure-based claims focus on protected amino acid components, position-specific side-chain selections, optional N-methylation, R/S stereochemistry, and in Formula (III) a covalent linking moiety between defined residue pairs.
Cyclic peptide of Formula (I) with constrained amino-acid selections
A cyclic peptide having the structure of Formula (I) or a pharmaceutically acceptable salt thereof, wherein A1 is an acyl or sulfonyl protected amino acid selected from the specified group or is an acyl protected amine; R4, R5, R6, R7, R8, R9, and R10 are selected from specified amino acid side chains; P1 is H, methyl, or an acetyl group and n is 0 or 1; p is 2, 3, or 4; each amino acid residue is optionally an N-methylated amino acid; and each amino acid residue can be in the R or S configuration.
Cyclic peptide of Formula (II) with constrained amino-acid selections
A cyclic peptide having the structure of Formula (II) or a pharmaceutically acceptable salt thereof, wherein A1 is an acyl or sulfonyl protected amino acid selected from the specified group or is an acyl protected amine; R4 through R10 and P1 are selected from specified amino acid side chains; P1 is H, methyl, or an acetyl group and n is 0 or 1; p is 2, 3, 4, 5, or 6; each amino acid residue is optionally an N-methylated amino acid; and each amino acid residue can be in the R or S configuration.
Cyclic peptide of Formula (III) with covalent linking requirement
A cyclic peptide having the structure of Formula (III) or a pharmaceutically acceptable salt thereof, wherein R3 is selected from the amino acid side chains of PRO and HIS; R6 is the amino acid side chain of a specified structure; R7 is selected from the amino acid side chains of ALA and GLU; R9 is selected from the amino acid side chain of a specified structure; R10 is selected from the amino acid side chain of THR; each amino acid residue is optionally an N-methylated amino acid; each amino acid residue can be in the R or S configuration; and either R3 and R7 or R6 and R10 are covalently bound by a linking moiety selected from specified linking moiety options.
Cyclic peptide selected from a group of cyclic peptide options
A cyclic peptide wherein the cyclic peptide is selected from the group consisting of specified cyclic peptide options.
Enumerated bicyclic polypeptide compound set
A bicyclic polypeptide compound selected from the group consisting of 341, 342, 343, 344, 345, 346, 347, 348, 349, 358, or 350.
Overall, the claim set covers cyclic peptides defined by Formula (I), Formula (II), and Formula (III), including residue selection, optional N-methylation, R/S stereochemistry, and a covalent linking requirement in Formula (III). The separate claims also cover selection-from-group cyclic peptide embodiments and enumerated bicyclic polypeptide compounds by compound number selection.
Stated Advantages
Inhibits the interaction between human PCSK9 and the EGF-A domain of human LDLR.
Inhibits PCSK9 activity in a subject.
Reduces low density lipoprotein (LDL) cholesterol in a subject.
Treats hypercholesterolemia.
Treats and/or prevents hypercholesterolemia.
Lower LDL cholesterol.
Documented Applications
Therapeutic methods to reduce low density lipoprotein (LDL) cholesterol in a subject by administering a therapeutically effective amount of the cyclic peptide.
Therapeutic methods for treating hypercholesterolemia and comorbid diseases selected from nephrotic syndrome, kidney failure, coronary artery disease, atherosclerosis, stroke, peripheral vascular disease, diabetes, or high blood pressure.
Therapeutic uses involving inhibition of human PCSK9 activity and inhibition of PCSK9–LDLR interaction at the EGF-A domain in a subject.
Pharmaceutical compositions with a pharmaceutically acceptable carrier comprising the cyclic peptide compounds.
Inhibiting the PCSK9–LDLR EGF-A interaction in subjects and cells.
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