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
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Publication Number
US-11530244-B2
Publication Date
2022-12-20
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 polycyclic peptide compounds of Formula (I), or pharmaceutically acceptable salts thereof. The compounds are defined by a variable substituent X selected from F, OH, Br, Me, OMe, Cl, and CF3, together with constrained selections for A1 and side-chain positions R1 through R5, optional L1, A2, and P1 features, optional N-methylation, optional R or S-enantiomer configuration, and n equal to 0, 1, 2, 3, or 4.
The disclosed content includes specific polycyclic peptide embodiments and structural depictions within the Formula (I) scaffold, including variants with fluorinated aryl or heteroaryl motifs, aromatic and heteroaromatic ring elements, and sulfur-containing linkers. The document also describes example compound sets and table-based embodiments corresponding to the defined polycyclic peptide family.
Functionally, the cyclic polypeptides are described as PCSK9-inhibitory peptide scaffolds that bind human PCSK9 and inhibit the PCSK9-LDLR interaction via the LDLR EGF-A domain. The patent further describes pharmaceutical compositions comprising a therapeutically effective amount of the cyclic polypeptide and at least one pharmaceutically acceptable carrier.
Claims Coverage
The claims coverage is centered on a Formula (I) polycyclic peptide scaffold with defined structural constraints, including X selection, residue side-chain selections, optional N-methylation, optional R/S enantiomer configuration, and n = 0-4. The claim set also includes therapeutic method claims directed to PCSK9 activity inhibition, blockade of the PCSK9-LDLR (EGF-A) interaction, LDL cholesterol reduction, and treatment of hypercholesterolemia, including specified comorbid diseases.
Polycyclic peptide of Formula (I) with defined substituents and residue constraints
A polycyclic peptide of Formula (I), or a pharmaceutically acceptable salt thereof, wherein X is selected from F, OH, Br, Me, OMe, Cl, and CF3; A1 is H or an acyl protected amine; R1 through R5 are selected from the listed amino acid side-chain groups; L1 is absent or A2 is absent or P1 is selected from H or acetyl; each amino acid residue is optionally N-methylated; each amino acid residue can be the R or S-enantiomer configuration; and n is 0, 1, 2, 3, or 4.
Inhibiting PCSK9 activity by administering the Formula (I) polycyclic peptide
A method of inhibiting PCSK9 activity in a subject in need thereof comprising administering a therapeutically effective amount of the polycyclic peptide of Formula (I).
Inhibiting PCSK9-LDLR (EGF-A) interaction by administering the Formula (I) polycyclic peptide
A method of inhibiting the interaction between PCSK9 and the EGF-A domain of LDLR in a subject in need thereof comprising administering a therapeutically effective amount of the polycyclic peptide of Formula (I).
Reducing LDL cholesterol level by administering the Formula (I) polycyclic peptide
A method of reducing low density lipoprotein (LDL) cholesterol level in a subject in need thereof comprising administering a therapeutically effective amount of the polycyclic peptide of Formula (I).
Treating hypercholesterolemia by administering the Formula (I) polycyclic peptide
A method of treating hypercholesterolemia in a subject in need thereof comprising administering a therapeutically effective amount of the polycyclic peptide of Formula (I).
Hypercholesterolemia with specified comorbid disease selection
The comorbid disease with hypercholesterolemia is selected from nephrotic syndrome, kidney failure, coronary artery disease, atherosclerosis, stroke, peripheral vascular disease, diabetes, and high blood pressure.
Overall, the claims provide protection for polycyclic peptides defined by Formula (I) with tightly constrained substituent and residue options and extend to therapeutic methods that use these peptides to inhibit PCSK9 activity, inhibit the PCSK9-LDLR (EGF-A) interaction, reduce LDL cholesterol, and treat hypercholesterolemia, including specified comorbid diseases.
Stated Advantages
Inhibits the PCSK9-LDLR interaction.
Inhibits PCSK9 activity.
Reduces low density lipoprotein (LDL) cholesterol level.
Treats hypercholesterolemia.
Increases LDLR on cell surfaces.
Reduces blood LDL cholesterol.
Treats and prevents hypercholesterolemia.
Treats diseases comorbid with hypercholesterolemia.
Documented Applications
Inhibiting PCSK9 activity in a subject in need thereof by administering a therapeutically effective amount of the polycyclic peptide of Formula (I).
Inhibiting the interaction between PCSK9 and the EGF-A domain of LDLR in a subject in need thereof by administering a therapeutically effective amount of the polycyclic peptide of Formula (I).
Reducing low density lipoprotein (LDL) cholesterol level in a subject in need thereof by administering a therapeutically effective amount of the polycyclic peptide of Formula (I).
Treating hypercholesterolemia in a subject in need thereof by administering a therapeutically effective amount of the polycyclic peptide of Formula (I), including cases with comorbid disease selected from nephrotic syndrome, kidney failure, coronary artery disease, atherosclerosis, stroke, peripheral vascular disease, diabetes, and high blood pressure.
Reducing LDL cholesterol in a subject.
Preventing hypercholesterolemia in a subject.
Treating diseases comorbid with hypercholesterolemia.
Inhibiting PCSK9 activity in a subject or cells.
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