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US 9,175,056 B2Granted
Bis-sulfhydryl macrocyclization systems
AssigneeAlleron Therapeutics, Inc.
InventorHuw M. Nash
Life of this patent
Estimating the term…
Abstract
Peptidomimetic macrocycles and methods for their preparation and use, as well as amino acid analogs and macrocycle-forming linkers, and kits useful in their production are described.
Claims21
A peptidomimetic macrocycle of Formula (I):
- wherein:
- each A, C, D, and E is independently a natural or non-natural amino acid;
- each B is independently a natural or non-natural 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-;
- each R3 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, unsubstituted or substituted with R5;
- L1, L3 and L4 are independently alkylene, alkenylene, alkynylene, heteroalkylene, heterocycloalkylene, or [—R4—K—R4—]n, each being unsubstituted or substituted with R5;
- L2 is a linker moiety unsubstituted or substituted with R5;
- each K is independently O, S, SO, SO2, CO, CO2, or CONR3;
- each R4 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;
- each R5 is independently halogen, alkyl unsubstituted or substituted with halogen, —OR6, —N(R6)2, —SR6, —SORE, —SO2R6, —CO2R6, a fluorescent label, a radioisotope or a therapeutic agent;
- each R6 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent label, a radioisotope or a therapeutic agent;
- R7 is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, unsubstituted or 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, unsubstituted or substituted with R5, or part of a cyclic structure with an E residue;
- v is an integer from 1-1000;
- w is an integer from 1-1000;
- x is an integer from 0-10;
- y is an integer from 0-10;
- z is an integer from 0-10;
- each n is independently an integer from 1-5;
- and
- x+y+z is at least 3,
- wherein at least one of A, B, C, D, or E, is an amino acid with a side chain thiol moiety.
20 more elements
A method for synthesizing a peptidomimetic macrocycle, comprising contacting a peptidomimetic precursor of Formula III:
- with a compound of formula X-L2-Y,
- wherein
- each A, C, D, and E is independently a natural or non-natural amino acid;
- each B is independently a natural or non-natural amino acid, amino acid analog,
- [—NH-L4-CO—], [—NH-L4-SO2—], or [—NH-L4-];
- R1 and R2 are independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, each of which except —H is unsubstituted or substituted with halo-;
- each R3 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, each of which except —H is unsubstituted or substituted with R5;
- L1, 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;
- L2 is a linker moiety unsubstituted or substituted with R5;
- each K is independently O, S, SO, SO2, CO, CO2, or CONR3;
- each R4 is independently_alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;
- each R5 is independently halogen, alkyl unsubstituted or substituted with halogen, —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, each of which except —H is unsubstituted or 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, each of which except —H is unsubstituted or substituted with R5, or part of a cyclic structure with an E residue;
- v is an integer from 1-1000;
- w is an integer from 1-1000;
- x is an integer from 0-10;
- y is an integer from 0-10;
- z is an integer from 0-10;
- and
- wherein at least one of A, B, C, D, or E, is an amino acid with a side chain thiol moiety;
- and X and Y are each independently a reactive group capable of reacting with a thiol group;
- and further wherein the contacting results in formation of the peptidomimetic macrocycle.
21 more elements
Dependencies are inferred from the claim text.