Macrocyclic peptidomimetics for alpha-helix mimicry

A method for synthesizing a macrocyclic peptidomimetic molecule, comprising contacting a precursor peptidomimetic molecule of Formula (IV):

• with a compound of Formula (V):
• Q2-L2-Y—H (V)
• wherein
• each of A, C, and D is independently a natural or non-natural amino acid;
• B is a natural amino acid, non-natural amino acid, an amino acid comprising at least one additional methylene groups between the amino and carboxyl group, an amino acid comprising an amino group which is a secondary or tertiary amine, an amino acid comprising a carboxy group replaced by an ester, [—NHN(R3)C(O)—], [—NH-L3-CO—], [—NH-L3-SO2—], or [—NH-L3-];
• Y is —NH—, —N(R4)—, —NHN(R4)—, —O—NH—, —O—, or —S—;
• L1, L2, and L3 are independently aliphatic, aryl, substituted aliphatic, substituted aryl, heteroatom-containing aliphatic, heteroatom-containing aryl, substituted heteroatom-containing aliphatic, substituted heteroatom-containing aryl groups, each being unsubstituted or substituted with R7;
• Q1 is selected from a group consisting of sulphydryl (—SH), amino (—NHR5), alkenyl (—C═CH2), alkynyl (—C≡CH), azido (—N3), keto (—C(O)R5—), and carboxy (—C(O)OH) group;
• Q2 is selected from a group consisting of —CH(R6)X, where X is F, Cl, Br, or I, amino (—NHR6), oxyamino (—ONH2), hydrazino (—NR6NH2), alkenyl (—C═CH2), alkynyl (—C≡CH), azido (—N3), keto (—C(O)R6—), and carboxy (—COOH) group;
• R1, R2, R3, R4, R5, and R6 are independently —H, aliphatic, substituted aliphatic, aryl, or substituted aryl group;
• each R7 is independently —H, an aliphatic, substituted aliphatic, an aryl, a substituted aryl group;
• x is an integer from 0-10;
• y is an integer from 0-10;
• z is an integer from 0-10;
• w is an integer from 1-1000;
• x+y+z is at least 3;
• and
• (LG) is a group that activates the terminal carboxylic acid carbonyl group toward nucleophilic substitution;
• wherein the contacting results in a covalent linkage being formed between the side-chain group, L1, and the C-terminal carboxyl group of the compound of Formula (IV) via a linker moiety, and
• wherein the macrocyclic peptidomimetic molecule comprises an α-helix.

A macrocyclic peptidomimetic molecule for use in the treatment of a p53/HDM2/HDMX-related disease in a subject, this macrocyclic peptidomimetic molecule having the structure of Formula (VII):

• wherein:
• each A, C, and D is independently a natural or non-natural amino acid;
• B is a natural amino acid, non-natural amino acid, an amino acid comprising at least one additional methylene groups between the amino and carboxyl group, an amino acid comprising an amino group which is a secondary or tertiary amine, an amino acid comprising a carboxy group replaced by an ester, [—NHN(R3)C(O)—], [—NH-L3-CO—], [—NH-L3-SO2—], or [—NH-L3-];
• Y is —NH—, —N(R4)—, —NHN(R4)—, —NH—O—, —O—, or —S—;
• Z is —SCHR6—, —CHR6S—, —C═C—, —N(R5)CO—, —CON(R6)—, —C(R5)═N(R6)—, —CH(R5)—NH(R6)—, —C(R5)═N—O—, —CH(R5)—NH—O—, —C(R5)═N—NH(R6)—, —CH(R5)—NH—NH(R6)—, or a triazole group;
• L1, L2, and L3 are independently aliphatic, aryl, substituted aliphatic, substituted aryl, heteroatom-containing aliphatic, heteroatom-containing aryl, substituted heteroatom-containing aliphatic, substituted heteroatom-containing aryl groups, each being unsubstituted or substituted with R7;
• R1, R2, R3, R4, R5, and R6 are independently —H, aliphatic, substituted aliphatic, aryl, or substituted aryl group;
• each R7 is independently —H, an aliphatic, substituted aliphatic, an aryl, and a substituted aryl group;
• x is an integer from 0-10;
• y is an integer from 0-10;
• z is an integer from 0-10;
• w is an integer from 1-1000;
• x+y+z is at least 3;
• and
• wherein the macrocyclic peptidomimetic molecule comprises an amino acid sequence which is at least 50% identical to an amino acid sequence selected from a group consisting of the amino acid sequences of SEQ ID NOS. 1 through 37.

A method for treating a p53/HDM2/HDMX-related disease in a subject, comprising:

• administering to a subject to be treated a macrocyclic peptidomimetic molecule having the structure of Formula (VII):
• wherein:
• each A, C, and D is independently a natural or non-natural amino acid;
• B is a natural amino acid, non-natural amino acid, an amino acid comprising at least one additional methylene groups between the amino and carboxyl group, an amino acid comprising an amino group which is a secondary or tertiary amine, an amino acid comprising a carboxy group replaced by an ester, [—NHN(R3)C(O)—], [—NH-L3-CO—], [—NH-L3-SO2—], or [—NH-L3-];
• Y is —NH—, —N(R4)—, —NHN(R4)—, —NH—O—, —O—, or —S—;
• Z is —SCHR6—, —CHR6S—, —C═C—, —N(R5)CO—, —CON(R6)—, —C(R5)═N(R6)—, —CH(R5)—NH(R6)—, —C(R5)═N—O—, —CH(R5)—NH—O—, —C(R5)═N—NH(R6)—, —CH(R5)—NH—NH(R6)—, or a triazole group;
• L1, L2, and L3 are independently aliphatic, aryl, substituted aliphatic, substituted aryl, heteroatom-containing aliphatic, heteroatom-containing aryl, substituted heteroatom-containing aliphatic, substituted heteroatom-containing aryl groups, each being unsubstituted or substituted with R7;
• R1, R2, R3, R4, R5, and R6 are independently —H, aliphatic, substituted aliphatic, aryl, or substituted aryl group;
• each R7 is independently —H, an aliphatic, substituted aliphatic, an aryl, and a substituted aryl group;
• x is an integer from 0-10;
• y is an integer from 0-10;
• z is an integer from 0-10;
• w is an integer from 1-1000;
• x+y+z is at least 3;
• and
• wherein the macrocyclic peptidomimetic molecule comprises an amino acid sequence which is at least 50% identical to an amino acid sequence selected from a group consisting of the amino acid sequences of SEQ ID NOS. 1 through 37.