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US 2025/0017940 A1Published application
Selective peptidomimetic modulators of cav2.2 (n-type) voltage-gated calcium channels and uses thereof
AssigneesNew York University, University of Pittsburgh—Of the Commonwealth System of Higher Education
InventorsRajesh KHANNA, Carlos J. CAMACHO
Life of this patent
Estimating the term…
Abstract
The present invention relates to compounds of Formula (I): where R1, R2, X, s, and p are as defined herein. The present invention also relates to compounds of Formula (II), Formula (III), and: where R1a, R1b, R1d, R2a, R2b, R3b, X, Z, Z1, Z2, s, and p are as defined herein. Methods of using these compounds to regulate Cav2.2.target double-stranded RNA and to treat diseases and disorders, e.g., chronic pain, are also disclosed.
Claims25
A compound of Formula (I):
- wherein
- X is a covalent bond or —C(O)—;
- p is 0, 1, 2, 3, or 4;
- s is 1 or 2;
- R1 is selected from the group consisting of C1-6 alkyl, benzyl, —NR3R4, monocyclic or bicyclic heteroaryl, and monocyclic or bicyclic heterocyclyl, wherein C1-6 alkyl, benzyl, monocyclic or bicyclic heteroaryl, and monocyclic or bicyclic heterocyclyl can be optionally substituted from 1 to 3 times with R5;
- R2 is independently at each occurrence a C1-6 alkyl;
- R3 is H;
- R4 is selected from the group consisting of —H, C1-6 alkyl, C3-8 cycloalkyl, monocyclic or bicyclic aryl, hereroaryl, heterocyclyl, —CH2-heterocyclyl, and —CH2-heteroaryl, wherein C1-6 alkyl, monocyclic or bicyclic aryl, heteroaryl, heterocyclyl, —CH2-heterocyclyl, and —CH2-heteroaryl can be optionally substituted from 1 to 3 times with R6;
- or
- R3 and R4 combine with the nitrogen atom to which they are attached to form a non-aromatic heterocyclyl, wherein the non-aromatic heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected independently from the group consisting of —H, C1-6 alkyl, and —NH—C(O)—Me;
- R5 is selected from the group consisting of —H, halogen, —OH, phenyl, C1-6 alkyl, benzyl, —OC1-6 alkyl, ═O, C3-8 cycloalkyl, monocyclic heteroaryl, wherein C1-6 alkyl and C3-8 cycloalkyl can be optionally substituted from 1 to 3 times with —NH2;
- R6 is independently selected from the group consisting of —H, —NMe2, C1-6 alkyl, —O—C1-6 alkyl, heteroaryl, —CH2-heterocyclyl, —CH2-heteroaryl, heterocyclyl, —OPh, C3-8 cycloalkyl, ═O, and heteroaryl, wherein —CH2-heterocyclyl, —CH2-heteroaryl, heterocyclyl, heteroaryl, and —OPh can be optionally substituted from 1 to 3 times with a substituent selected independently from the group consisting of —H, C1-6 alkyl, C3-8 cycloalkyl, —OH, ═O, halogen, and —SC1-6 alkyl,
- or a solvate, or a pharmaceutically acceptable salt thereof.
10 more elements
(canceled)
(canceled)
(canceled)
A compound of Formula (II):
- wherein
- R1a is selected from the group consisting of —OH, —OC1-6 alkyl, and —NHR3a;
- R2a is selected from the group consisting of —H, —C(O)—R4a, —C(Y)C1-6 alkyl, —C(Y)C3-8 cycloalkyl, —C(O)OC1-6 alkyl, —C(Y)aryl, —C(Y)NH-aryl, —C(Y)NH—CH2-aryl, —C(Y)NHC3-8 cycloalkyl, and —S(O)2aryl, wherein —C(O)—R4a, —C(Y)C1-6 alkyl, —C(Y)C3-8 cycloalkyl, —C(O)OC1-6 alkyl, —C(Y)aryl, —C(Y)NH-aryl, —C(Y)NH—CH2-aryl, —C(Y)NHC3-8 cycloalkyl, and —S(O)2aryl can be optionally substituted from 1 to 3 times with a substituent selected independently from C1-6 alkyl and —NH2,
- R3a is selected from C1-6 alkyl or monocyclic or bicyclic aryl, wherein C1-6 alkyl and monocyclic and bicyclic aryl can be optionally substituted from 1 to 3 times with a substituent selected independently from —COOH and —NO2;
- R4a is non-aromatic heterocyclyl optionally substituted with —C(O)OC1-6 alkyl;
- Y is O or S,
- or a solvate, or a pharmaceutically acceptable salt thereof.
4 more elements
A compound of Formula (III):
- is optional and if present is
- is a single or a double bond;
- Z is C or N;
- Z1 is CH, CH2, N, or a covalent bond;
- Z2 is CH2 or a covalent bond;
- n is 0, 1, or 2;
- R1b is selected from the group consisting of —H, C1-6 alkyl, C3-8 cycloalkyl, aryl, and benzyl, wherein C1-6 alkyl, aryl, and benzyl can be optionally substituted with a substituent selected from —CN, —OC1-6 alkyl, heteroaryl, and non-aromatic heterocyclyl;
- R2b is selected from the group consisting of —H, C1-6 alkyl, C3-8 cycloalkyl, aryl, and benzyl, wherein C1-6 alkyl, aryl, and benzyl can be optionally substituted with a substituent selected from —CN, —OC1-6 alkyl, heteroaryl, and non-aromatic heterocyclyl;
- R3b is —H or C1-6 alkyl,
- or a solvate, or a pharmaceutically acceptable salt thereof.
7 more elements
-21. (canceled)
A compound of Formula (IV):
- wherein
- R1d is —COOC1-6 alkyl, —C(O)aryl, or —C(O)heteroaryl, wherein —C(O)aryl can be optionally substituted with —NO2,
- or a solvate, or a pharmaceutically acceptable salt thereof.
23-24. (canceled)
A compound selected from the group consisting of
- or a solvate, or a pharmaceutically acceptable salt thereof.
A method of identifying one or more compounds capable of regulating Cav2.2 comprising:
- providing a CBD3 peptide;
- identifying one or more stable structural motif(s) of the CBD3 peptide;
- providing one or more pharmacophore models that map the stable structural motif of the CBD3 peptide or it's properties into said pharmacophore models;
- providing one or more compounds;
- screening each of said pharmacophore models against said compounds;
- and
- selecting one or more compounds that have a highest Cav2.2 recognition score for future testing.
4 more elements
Dependencies are inferred from the claim text.