Novel Cyclic Peptides Trapping Interleukin-1β to Relieve Inflammatory and Atherosclerotic Cardiovascular Disease

Abstract

This patent application discloses a novel class of cyclic peptides, represented by Formula I, designed to selectively trap Interleukin-1β (IL-1β). These peptides offer promising therapeutic potential for slowing the progression of atherosclerotic cardiovascular disease (ASCVD).

Important Compound Classes

Title

A cyclic peptide for trapping interleukin-1 beta

Patent Publication Number

WO 2024215820 A2 URL: https://patents.google.com/patent/WO2024215820A2/en

Publication Date

October 17, 2024

Priority Application

US 63/496,260

Priority Date

April 14, 2023

Inventors

Guo, Y.; Hanisak, J.; Hickey, J. L.; Kekec, A.; Kerekes, A. D.; Lo, M. M. -C.; Mak, V. W.; Plummer, C. W.; Silverman, S. M.; Colarusso, S.; Nizi, E.; Pavone, F.

Assignee Company

Merck Sharp & Dohme LLC, 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.

Disease Area

Inflammatory disorders, Atherosclerotic cardiovascular disease (ASCVD)

Biological Target

Interleukin-1β (IL-1β)

Summary

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of mortality and has drawn considerable attention to its underlying mechanisms. Strong evidence has established the association between inflammation and increased risk of cardiovascular disease, suggesting the important role of interleukin-1β (IL-1β) in human ASCVD. IL-Ιβ is a 17.5 kDa proinflammatory cytokine that induces IL-6 production, thereby activating downstream inflammatory pathways. Consequently, IL-1β is considered as an effective target to reduce cardiovascular disease progression.

Currently, Canakinumab, an IL-1β-neutralizing therapy, is the only verified therapy. However, effective pharmaceuticals for ASCVD remain limited due to the complexity of the inflammatory process in atherosclerosis. This highlights the urgent need for novel therapeutic agents capable of targeting or trapping IL-1β to mitigate ASCVD progression.

This application describes a novel class of cyclic peptides capable of trapping IL-1β, along with their preparation, use, and potential therapeutic applications. These peptides are particularly suitable for treating disorders or conditions associated with IL-1β mediating inflammatory with a specific focus on ASCVDs.

Definitions

R¹ = R^1e–C­(O)­NH–CH₂CH₂–O–, C₁–C₄ alkyl, halo, or C¹;

R^1e- is

(a) C₁–C₄ alkyl; or C₁₁; wherein C^Y1 is

(i) C₃–C₆ cycloalkyl; (ii) phenyl; or (iii) a 5- to 6-membered monocyclic heteroaryl, wherein said heteroaryl contains 1 to 2 heteroatoms independently selected from the group consisting of N, O, and S;

wherein C^Y1 is unsubstituted or substituted by 1 to 3 R^Y1 substituents selected from the group consisting of C₁–C₃ alkyl, halo, and piperazinyl;

C¹ is

(i) a 5- to 6-membered monocyclic aryl or heteroaryl, wherein said heteroaryl contains 1 to 2 heteroatoms independently selected from the group consisting of N, O, and S; (ii) a 3- to 6-membered monocyclic or a 5- to 8-membered bicyclic cycloalkyl; or (iii) a 5- to 6-membered monocyclic, saturated heterocycloalkyl containing 1 to 2 heteroatoms independently selected from the group consisting of N, O, and S;

wherein C¹ is unsubstituted or substituted by 1 to 3 R^C1 substituents independently selected from the group consisting of halo. C₁–C₃ alkyl. C₁–C₃ fluoroalkyl, carboxy, C₁–C₃ alkoxy, C₂–C₃ acyl, −C­(O)­NH₂. and −C­(O)­N­(CH₃)₂;

R² is

(i) a 5- to 6-membered monocyclic aryl or heteroaryl, wherein said heteroaryl contains 1 to 2 heteroatoms independently selected from the group consisting of N, O, and S; and (ii) a 3- to 8-membered mono- or bicyclic cycloalkyl;

wherein R² is unsubstituted or substituted by 1 to 3 R^2a substituents independently selected from the group consisting of halo, amino, hydroxy, C₁–C₃ alkyl, C₁–C₃ fluoroalkyl, and C₁–C₃ alkoxy;

R^2b = H or hydroxy;

R³ = F or hydroxy;

R⁴ is

(i) naphthyl; or (ii) a 9- to 10-membered heteroaryl, wherein said heteroaryl contains 1 to 2 heteroatoms independently selected from the group consisting of N, O. and S;

wherein R⁴ is unsubstituted or substituted by 1 to 2 R^4a substituents independently selected from the group consisting of halo;

R^5a or R^5a = H, C₁–C₃ alkyl, H₂N­(CH₂)_m–, or HOCH₂–; or, alternatively R^5a and R^5b together with the carbon atom to which they attached, form a C₃–C₆ cycloalkyl or a 4- to 6-membered saturated heterocycloalkyl containing one N atom;

Each of R^6a and R^6b is independently H, −(CH₂)_n1CH₃, −(CH₂)_n2–OH, or −(CH₂)_n2CO₂H;

R^7a or R^7b = H, C₁–C₃ alkyl, HOCH₂–, H₂N­(CH₂)_p–, HO₂CCH₂–, H₂NC­(O)­CH₂–, CH₃OCH₂–, or PhCH₂–; or, alternatively R^7a and R^7b, together with the carbon atom to which they are attached, form a 4- to 6-membered saturated heterocycloalkyl containing one N atom;

R^8a = HO-(CH₂)_q–, CH₃–O–(CH₂)_q–, CH₃CH₂–O–(CH₂)_q– PhCH₂–O–(CH₂)_q–. C₁–C₃ alkyl, C₁–C₃ fluoroalkyl, H₂N–(CH₂)_r–, (CH₃)₃N–(CH₂)_f–, H₂NC­(NH)­N­(H)–(CH₂)_f–, H₂NC­(O)­N­(H)–(CH₂)_r–, HO₂C–(CH₂)_r–, (CH₃)­SO₂–(CH₂)_r–, C^8a or C^8a–CH₂–;

wherein C^8a is

(i) a 5- to 6-membered monocyclic aryl or heteroaryl, wherein said heteroaryl contains 1 to 2 heteroatoms independently selected from the group consisting of N, O, and S; (ii) a 5- to 6-membered monocyclic, saturated heterocycloalkyl, wherein said heterocycloalkyl contains 1 to 2 heteroatoms independently selected from the group consisting of N, O, and S; or (iii) a C₃–C₆ cycloalkyl;

wherein C^8a is unsubstituted or substituted by 1 to 3 R^C8a substituents independently selected from the group consisting of halo, amino, hydroxy, C₁–C₃ alkyl, C₁–C₃ fluoroalkyl. C₁–C₃ alkoxy, H₂N–(CH₂)_s–, H₂NC­(O)–(CH₂)_s–, H₂C = CH–CH₂O–, and phenyl;

R^8b = H, methyl, or hydroxy;

R⁹ = HO–(CH₂)_t–. H₂N-(CH₂)_u–. H₂NC­(NH)­N­(H)–(CH₂)_u–, H₂NC­(O)­N­(H)-(CH₂)_u–, or C⁹;

C⁹ is a 5- to 6-membered saturated heterocycloalkyl containing 1 to 2 heteroatoms independently selected from the group consisting of N, O, and S;

wherein C⁹ is unsubstituted or substituted by 1 to 2 R^C9 moieties independently selected from the group consisting of halo, C₁–C₃ alkyl, C₁–C₃ fluoroalkyl, and C₁–C₃ alkoxy;

R¹⁰ = H or methyl;

R¹¹ = H, −CH₂–C¹¹, or −CH₂–C¹¹–C^a;

C¹¹ is

(i) phenyl; or (ii) a 5- to 6-membered monocyclic heteroaryl, wherein said heteroaryl contains 1 to 2 heteroatoms independently selected from the group consisting of N, O, and S;

wherein C¹¹ is unsubstituted or substituted by 1 to 3 R^C11 substituents independently selected from the group consisting of halo, hydroxy, amino, C₁–C₃ alkyl, C₁–C₃ fluoroalkyl, carboxy, C₁–C₃ alkoxy, and C₂–C₃ acyl;

C^a is a 5- to 6-membered monocyclic heteroaryl, wherein said heteroaryl contains 1 to 2 heteroatoms independently selected from the group consisting of N, O, and S;

wherein C^a is unsubstituted or substituted by 1 to 3 R^Ca substituents independently selected from the group consisting of halo, hydroxy, amino, C₁–C₃ alkyl, C₁–C₃ fluoroalkyl, carboxy, C₁–C₃ alkoxy, and C₂–C₃ acyl;

R¹² = H or −CH₂C¹²;

C¹² is

(i) phenyl; or (ii) a 5- to 6-membered monocyclic heteroaryl, wherein said heteroaryl contains 1 to 2 heteroatoms independently selected from the group consisting of N, O, and S;

wherein C¹² is unsubstituted or substituted by 1 to 3 R^C12 substituents independently selected from the group consisting of halo, hydroxy, amino. C₁–C₃ alkyl. C₁–C₃ fluoroalkyl, carboxy, C₁–C₃ alkoxy, and C₂–C₃ acyl;

R¹³ = H or methyl;

R¹⁴ = halo;

R¹⁵ = −OH or −ΝΗ₂;

R¹⁶ = halo, hydroxy, C1–C3 alkyl, C1–C3 fluoroalkyl, or C1–C3 alkoxy;

R¹⁷ = H, hydroxy, or methyl;

X,¹ and X,² are independently C­(H) or N; and

X³ and X⁴ are independently C­(H), C­(Cl), C­(F) or N: or a pharmaceutically acceptable salt thereof.

Key Structures

Biological Assay

IL-6 assay in human lung fibroblast MRC5 cells (ATCC CCL-171) was employed to evaluate the functional activity of the related peptides. IL-6 secretion levels were determined using the human AlphaLISA IL-6 kit (PerkinElmer AL223F).

Biological Data

IC₅₀ values related to IL-1β inhibition are listed below.

Claims

Total claims: 39

Compound claims: 31

Pharmaceutical composition claims: 4

Medicament claims: 4

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The authors declare no competing financial interest.