Peptidomimetic macrocycles

A peptidomimetic macrocycle of Formula:

• wherein:
• each of Xaa3, Xaa5, Xaa6, Xaa7, Xaa8, Xaa9, and Xaa10 is individually an amino acid, wherein at least three of Xaa3, Xaa5, Xaa6, Xaa7, Xaa8, Xaa9, and Xaa10 are the same amino acid as the amino acid at the corresponding position of the sequence Phe3-X4-Glu5-Tyr6-Trp7-Ala8-Gln9-Leu10/Cba10-X11-Ala12, where each X is an amino acid;
• each D and E is independently an amino acid;
• R1 and R2 are independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-;
• or at least one of R1 and R2 forms a macrocycle-forming linker L′ connected to the alpha position of one of said D or E amino acids;
• each L or L′ is independently a macrocycle-forming linker of the formula -L1-L2-;
• L1 and L2 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [—R4—K—R4—]n, each being optionally substituted with R5;
• R3 is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5;
• each R4 is alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;
• each K is O, S, SO, SO2, CO, CO2, or CONR3;
• each R5 is independently halogen, alkyl, —OR6, —N(R6)2, —SR6, —SOR6, —SO2R6, —CO2R6, a fluorescent moiety, a radioisotope or a therapeutic agent;
• each R6 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;
• R7 is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with a D residue;
• R8 is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with an E residue;
• v is an integer from 1-1000, for example 1-500, 1-200, 1-100, 1-50, 1-30, 1-20, or 1-10;
• w is an integer from 3-1000, for example 3-500, 3-200, 3-100, 3-50, 3-30, 3-20, or 3-10;
• and
• n is an integer from 1-5.

A peptidomimetic macrocycle comprising an amino acid sequence which is at least about 60% identical to an amino acid sequence chosen from the group consisting of the amino acid sequences in Table 1, Table 1a, Table 1b, or Table 1c, wherein the peptidomimetic macrocycle has the formula:

• Formula (I)
• wherein:
• each A, C, D, and E is independently an amino acid;
• B is an amino acid,
• [—NH-L3-CO—], [—NH-L3-SO2—], or [—NH-L3-];
• R1 and R2 are independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-;
• or at least one of R1 and R2 forms a macrocycle-forming linker L′ connected to the alpha position of one of said D or E amino acids;
• R3 is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5;
• each L or L′ is independently a macrocycle-forming linker of the formula -L1-L2-;
• L1 and L2 and L3 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [—R4—K—R4—]n, each being optionally substituted with R5;
• each R4 is alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;
• each K is O, S, SO, SO2, CO, CO2, or CONR3;
• each R5 is independently halogen, alkyl, —OR6, —N(R6)2, —SR6, —SOR6, —SO2R6, —CO2R6, a fluorescent moiety, a radioisotope or a therapeutic agent;
• each R6 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;
• R7 is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with a D residue;
• R8 is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with an E residue;
• v and w are independently integers from 1-1000, for example 1-500, 1-200, 1-100, 1-50, 1-30, 1-20, or 1-10;
• u is an integer from 1-10, for example 1-5, 1-3 or 1-2;
• x, y and z are independently integers from 0-10, for example the sum of x+y+z is 2, 3, or 6;
• n is an integer from 1-5;
• and
• wherein the peptidomimetic macrocycle is not a peptidomimetic macrocycle of Tables 2a or 2b.

A peptidomimetic macrocycle comprising an amino acid sequence which is at least about 60% identical to an amino acid sequence chosen from the group consisting of the amino acid sequences in Table 1, Table 1a, Table 1b, or Table 1c, wherein the peptidomimetic macrocycle has the formula:

• Formula (I)
• wherein:
• each A, C, D, and E is independently an amino acid;
• B is an amino acid,
• [—NH-L3-CO—], [—NH-L3-SO2—], or [—NH-L3-];
• R1 and R2 are independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-;
• or at least one of R1 and R2 forms a macrocycle-forming linker L′ connected to the alpha position of one of said D or E amino acids;
• R3 is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5;
• each L or L′ is independently a macrocycle-forming linker of the formula -L1-L2-;
• L1 and L2 and L3 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [—R4—K—R4—]n, each being optionally substituted with R5;
• each R4 is alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;
• each K is O, S, SO, SO2, CO, CO2, or CONR3;
• each R5 is independently halogen, alkyl, —OR6, —N(R6)2, —SR6, —SOR6, —SO2R6, —CO2R6, a fluorescent moiety, a radioisotope or a therapeutic agent;
• each R6 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;
• R7 is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with a D residue;
• R8 is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with an E residue;
• v and w are independently integers from 1-1000, for example 1-500, 1-200, 1-100, 1-50, 1-30, 1-20, or 1-10;
• u is an integer from 1-10, for example 1-5, 1-3 or 1-2;
• x, y and z are independently integers from 0-10, for example the sum of x+y+z is 6;
• n is an integer from 1-5;
• wherein w>2 and each of the first two amino acid represented by E comprises an uncharged side chain or a negatively charged side chain,
• with the proviso that the peptidomimetic macrocycle is not a peptidomimetic macrocycle of Table 2a and does not have the sequence of:
• Ac-RTQATF$r8NQWAibAN1e$TNAibTR-NH2,
• Ac-$r8SQQTFS$LWRLLAibQN-NH2,
• Ac-QSQ$r8TFSNLW$LLAibQN-NH2,
• Ac-QS$rSQTFStNLW$LLAibQN-NH2, or
• Ac-QSQQ$r8FSNLWR$LAibQN-NH2,
• wherein Aib represents 2-aminoisobutyric acid, $ represents an alpha-Me S5-pentenyl-alanine olefin amino acid connected by an all-carbon crosslinker comprising one double bond, $r5 represents an alpha-Me R5-pentenyl-alanine olefin amino acids connected by an all-carbon comprising one double bond, and $r8 represents an alpha-Me R8-octenyl-alanine olefin amino acid connected by an all-carbon crosslinker comprising one double bond.

A peptidomimetic macrocycle comprising an amino acid sequence which is at least about 60% identical to an amino acid sequence chosen from the group consisting of the amino acid sequences in Table 1, Table 1a, Table 1b, or Table 1c, wherein the peptidomimetic macrocycle has the formula:

• Formula (I)
• wherein:
• each A, C, D, and E is independently an amino acid;
• B is an amino acid,
• [—NH-L3-CO—], [—NH-L3-SO2—], or [—NH-L3-];
• R1 and R2 are independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-;
• or at least one of R1 and R2 forms a macrocycle-forming linker L′ connected to the alpha position of one of said D or E amino acids;
• R3 is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5;
• each L or L′ is independently a macrocycle-forming linker of the formula -L1-L2-;
• L1 and L2 and L3 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [—R4—K—R4—]n, each being optionally substituted with R5;
• each R4 is alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;
• each K is O, S, SO, SO2, CO, CO2, or CONR3;
• each R5 is independently halogen, alkyl, —OR6, —N(R6)2, —SR6, —SOR6, —SO2R6, —CO2R6, a fluorescent moiety, a radioisotope or a therapeutic agent;
• each R6 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;
• R7 is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with a D residue;
• R8 is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with an E residue;
• v and w are independently integers from 1-1000, for example 1-500, 1-200, 1-100, 1-50, 1-30, 1-20, or 1-10;
• u is an integer from 1-10, for example 1-5, 1-3 or 1-2;
• x, y and z are independently integers from 0-10, for example the sum of x+y+z is 6;
• n is an integer from 1-5;
• and
• w>2, wherein the third amino acid represented by E comprises a large hydrophobic side chain,
• with the proviso that the peptidomimetic macrocycle is not a peptidomimetic macrocycle of Table 2a and does not have the sequence of:
• Ac-Q$r8QQTFSN$WRLLAibQN-NH2.

A method of preparing a composition comprising a peptidomimetic macrocycle of Formula (I):

• comprising an amino acid sequence which is about 60% to about 100% identical to an amino acid sequence selected from the group consisting of the amino acid sequences in Table 1, Table 1a, Table 1b, or Table 1c, the method comprising treating a compound of Formula (II)
• with a catalyst to result in the compound of Formula I
• wherein in the compound(s) of Formulae (I) and (II)
• each A, C, D, and E is independently an amino acid;
• each B is independently an amino acid,
• [—NH-L3-CO—], [—NH-L3-SO2—], or [—NH-L3-];
• each R1 and R2 are independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halogen;
• or at least one of R1 and R2 forms a macrocycle-forming linker L′ connected to the alpha position of one of the D or E amino acids;
• each R3 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5;
• each L′ is independently a macrocycle-forming linker of the formula -L1-L2-;
• each L1, L, and L3 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [—R4—K—R4′-]n, each being optionally substituted with R5;
• each R4 and R4′, is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;
• each K is independently O, S, SO, SO2, CO, CO2, or CONR3;
• each R5 is independently halogen, alkyl, —OR6, —N(R6)2, —SR6, —SOR6, —SO2R6, —CO2R6, a fluorescent moiety, a radioisotope or a therapeutic agent;
• each R6 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;
• each R7 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with a D residue;
• each R8 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with an E residue;
• each v and w are independently integers from 1-1000;
• u is an integer from 1-10;
• each x, y and z are independently integers from 0-10;
• each n is independently an integer from 1-5;
• each o is independently an integer from 1 to 15;
• each p is independently an integer from 1 to 15;
• “(E)” indicates a trans double bond;
• and
• one or more of the amino acids A, C and/or B when B is an amino acid, present in the compounds of Formulae (I) and (II), has a side chain bearing a protecting group.