Triazole macrocycle systems

Patent metadata

Field	Value
Publication number	US-9493509-B2
Application number	US-201514677679-A
Country	US
Kind code	B2
Filing date	Apr 2, 2015
Priority date	Feb 23, 2007
Publication date	Nov 15, 2016
Grant date	Nov 15, 2016

Abstract

The present invention provides novel 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. Macrocycles of the invention include triazole moieties that crosslink amino acid side chains. The cross links can stabilize a secondary structure of a peptidomimetic macrocycle, such as an α-helix.

First claim

What is claimed is:

1. 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, amino acid analog,

[—NH-L 3 -CO—], [—NH-L 3 -SO 2 —], or [—NH-L 3 -];
R 1 and R 2 are independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, each non-H group being unsubstituted or substituted with halo-;
each R 3 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, each non-H group being optionally substituted with R 5 ;
L is a triazole-containing macrocycle-forming linker of the formula

each L 1 , L 2 , and L 3 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [—R 4 —K—R 4 -] n , each being optionally substituted with R 5 ;
each R 4 is alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;
each K is O, S, SO, SO 2 , CO, C(═O)—O—[[CO 2 ]], or CONR 3 ;
each R 5 is independently halogen, alkyl, —OR 6 , —N(R 6 ) 2 , —SR 6 , —SOR 6 , —SO 2 R 6 , —CO 2 R 6 , a fluorescent moiety, a radioisotope or a therapeutic agent;
each R 6 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;
R 7 is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, each non-H group being optionally substituted with R 5 , or part of a cyclic structure with a D residue;
R 8 is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, each non-H group being optionally substituted with R 5 , 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+y+z is 3, 4, 5, 6, 7, 8, 9, or 10; and
n is an integer from 1-5.

2. The peptidomimetic macrocycle of claim 1 , wherein x+y+z is 3.

3. The peptidomimetic macrocycle of claim 1 , wherein x+y+z is 6.

4. The peptidomimetic macrocycle of claim 1 , wherein L is

5. The peptidomimetic macrocycle of claim 1 , wherein L is

6. The peptidomimetic macrocycle of claim 1 , wherein at least one of R 1 and R 2 is alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, each non-H group being unsubstituted or substituted with halo-.

7. The peptidomimetic macrocycle of claim 1 , wherein R 1 and R 2 are independently alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, each non-H group being unsubstituted or substituted with halo-.

8. The peptidomimetic macrocycle of claim 1 , wherein at least one of R 1 and R 2 is alkyl, each non-H group being unsubstituted or substituted with halo-.

9. The peptidomimetic macrocycle of claim 1 , wherein R 1 and R 2 are independently alkyl, each non-H group being unsubstituted or substituted with halo-.

10. The peptidomimetic macrocycle of claim 1 , wherein at least one of R 1 and R 2 is methyl.

11. The peptidomimetic macrocycle of claim 1 , wherein R 1 and R 2 are methyl.

12. The peptidomimetic macrocycle of claim 1 , wherein at least one of D and E is attached to an additional macrocycle-forming linker.

13. The peptidomimetic macrocycle of claim 1 , wherein a secondary structure of the peptidomimetic macrocycle is more stable than a corresponding secondary structure of a corresponding non-macrocyclic polypeptide.

14. The peptidomimetic macrocycle of claim 1 , wherein the peptidomimetic macrocycle exhibits increased thermal stability compared to a corresponding non-macrocyclic polypeptide.

15. The peptidomimetic macrocycle of claim 1 , wherein the peptidomimetic macrocycle exhibits increased biological activity compared to a corresponding non-macrocyclic polypeptide.

16. The peptidomimetic macrocycle of claim 1 , wherein the peptidomimetic macrocycle exhibits increased resistance to proteolytic degradation compared to a corresponding non-macrocyclic polypeptide.

17. The peptidomimetic macrocycle of claim 1 , wherein the peptidomimetic macrocycle exhibits increased ability to penetrate living cells compared to a corresponding non-macrocyclic polypeptide.

18. The peptidomimetic macrocycle of claim 1 , wherein the peptidomimetic macrocycle comprises an α-helix.

19. The peptidomimetic macrocycle of claim 18 , wherein the α-helix comprises from 1 turn to 5 turns.

20. The peptidomimetic macrocycle of claim 18 , wherein the α-helix is more stable than an α-helix of a corresponding non-macrocyclic polypeptide.

21. The peptidomimetic macrocycle of claim 18 , wherein the macrocycle-forming linker spans from 1 turn to 5 turns of the α-helix.

22. The peptidomimetic macrocycle of claim 18 , wherein the macrocycle-forming linker spans approximately 1 turn to approximately 2 turns of the α-helix.

23. The peptidomimetic macrocycle of claim 18 , wherein the length of the macrocycle-forming linker is approximately equal to the length of from about 6 carbon-carbon bonds to about 14 carbon-carbon bonds.

Assignees

• Aileron Therapeutics Inc

Inventors

• Nash Huw M

Classifications

• C07K1/113

  without change of the primary structure · CPC title

• C07K14/001

  by chemical synthesis · CPC title

• C07C271/22

  to carbon atoms of hydrocarbon radicals substituted by carboxyl groups · CPC title

• C07K14/47 Primary

  from mammals · CPC title

• C07K7/08

  having 12 to 20 amino acids (gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68) · CPC title