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US 2013/0210745 A1Published application
Triazole-crosslinked and thioether-crosslinked peptidomimetic macrocycles
AssigneeAileron Therapeutics, Inc.
InventorsVincent Guerlavais, Christopher R. Conlee, Scott Paul Lentini
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Abstract
Provided herein are peptidomimetic macrocycles and methods of using such macrocycles for the treatment of disease.
Claims39
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-His5-Tyr6-Trp7-Ala8-Gln9-Leu10-X11-Ser12, 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 and L′ is independently a macrocycle-forming linker of the formula
- L1 and L2 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [—R4—K—R4—]n, each being optionally substituted with R5;
- each R3 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5;
- each 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 —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;
- each R7 is independently —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;
- each R8 is independently —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.
15 more elements
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-His5-Tyr6-Trp7-Ala8-Gln9-Leu10-X11-Ser12, 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;
- L1, L2, and L3 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene or [—R4—K—R4-]n, each being unsubstituted or substituted with R5;
- each K is O, S, SO, SO2, CO, CO2, or CONR3;
- each R4 is alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;
- 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.
16 more elements
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 Tables 4, 4a, or 4b, wherein the peptidomimetic macrocycle has the formula:
- 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;
- each L and L′ is independently a macrocycle-forming linker of the formula
- L1, 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 R3 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5;
- each 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 —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;
- each R7 is independently —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;
- each R8 is independently —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;
- and
- n is an integer from 1-5.
17 more elements
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 and L′ is independently a macrocycle-forming linker of the formula
- 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.
15 more elements
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 Tables 6 or 6a, wherein the peptidomimetic macrocycle has the formula:
- wherein:
- each A, C, D, and E is independently an amino acid;
- B is an amino acid,
- [—NH-L4-CO-], [—NH-L4-SO2-], or [—NH-L4-];
- 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;
- L1, L2, L3 and L4 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene or [—R4—K—R4-]n, each being unsubstituted or substituted with R5;
- each K is O, S, SO, SO2, CO, CO2, or CONR3;
- each R4 is alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;
- 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;
- and
- n is an integer from 1-5,
- wherein the peptidomimetic macrocycle is not a peptidomimetic macrocycle of Table 7, Table 7a or Table 7b.
17 more elements
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;
- L1, L2, and L3 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene or [—R4—K—R4-]n, each being unsubstituted or substituted with R5;
- each K is O, S, SO, SO2, CO, CO2, or CONR3;
- 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 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.
14 more elements
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-His5-Tyr6-Trp7-Ala8-Gln9-Leu10-X11-Ser12, 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 and L′ is independently a macrocycle-forming linker of the formula
- L1 and L2 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [—R4—K—R4-]n, each being optionally substituted with R5;
- each R3 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5;
- each 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 —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;
- each R7 is independently —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;
- each R8 is independently —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;
- each R9 is independently alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, or heterocyclyl group, unsubstituted or optionally substituted with Ra and/or Rb;
- 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.
16 more elements
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 and L′ is independently a macrocycle-forming linker of the formula
- 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;
- each R9 is independently alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, or heterocyclyl group, unsubstituted or optionally substituted with Ra and/or Rb;
- 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.
16 more elements
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 Tables 4, 4a, or 4b, wherein the peptidomimetic macrocycle has the formula:
- 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;
- each L and L′ is independently a macrocycle-forming linker of the formula
- L1, 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 R3 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5;
- each 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 —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;
- each R7 is independently —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;
- each R8 is independently —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;
- each R9 is independently alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, or heterocyclyl group, unsubstituted or optionally substituted with Ra and/or Rb;
- 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;
- and
- n is an integer from 1-5.
18 more elements
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-His5-Tyr6-Trp7-Ala8-Gln9-Leu10-X11-Ser12, 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;
- L1, L2, and L3 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene or [—R4—K—R4—]n, each being unsubstituted or substituted with R5;
- each K is O, S, SO, SO2, CO, CO2, or CONR3;
- each R4 is alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;
- 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.
16 more elements
The peptidomimetic macrocycle of any preceding claim, wherein each E is independently an amino acid selected from Ala (alanine), D-Ala (D-alanine), Aib (α-aminoisobutyric acid), Sar (N-methyl glycine), and Ser (serine).
The peptidomimetic macrocycle of any preceding claim, wherein [D]v is -Leu1-Thr2.
The peptidomimetic macrocycle of any preceding claim, wherein the peptidomimetic macrocycle is not a macrocycle of Table 5, Table 7, Table 7a, or Table 7b.
The peptidomimetic macrocycle of any preceding claim, wherein each E is Ser or Ala or an analog thereof.
The peptidomimetic macrocycle of any preceding claim, comprising at least one amino acid which is an amino acid analog.
A method of treating cancer in a subject comprising administering to the subject a peptidomimetic macrocycle of any one of the preceding claims.
A method of modulating the activity of p53 and/or MDM2 and/or MDMX in a subject comprising administering to the subject a peptidomimetic macrocycle any one of the preceding claims.
A method of antagonizing the interaction between p53 and MDM2 and/or between p53 and MDMX proteins in a subject comprising administering to the subject a peptidomimetic macrocycle any one of the preceding claims.
Dependencies are inferred from the claim text.