Bis-sulfhydryl macrocyclization systems

Patent metadata

Field	Value
Publication number	US-9675661-B2
Application number	US-201514852368-A
Country	US
Kind code	B2
Filing date	Sep 11, 2015
Priority date	Dec 14, 2006
Publication date	Jun 13, 2017
Grant date	Jun 13, 2017

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.

First claim

What is claimed is:

1. A pharmaceutical composition comprising 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 4 -CO—], [—NH-L 4 -SO 2 —], or [—NH-L 4 -];
R 1 and R 2 are independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-;
each R 3 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, unsubstituted or substituted with R 5 ;
L 1 , L 3 and L 4 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene or [—R 4 —K—R 4 —]n, each being unsubstituted or substituted with R 5 ;
L 2 is alkylene, alkenylene, alkynylene, heteroalkylene, heterocycloalkylene, or [—R 4 —K—R 4 —]n, each being unsubstituted or substituted with R 5 ;
each K is independently O, S, SO, SO 2 , CO, CO 2 , or CONR 3 ;
each R 4 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;
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, unsubstituted or 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, unsubstituted or 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 is an integer from 0-10;
y is an integer from 0-10;
z is an integer from 0-10; and
n is an integer from 1-5.

2. The pharmaceutical composition of claim 1 , wherein at least one of R 1 and R 2 is alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-.

3. The pharmaceutical composition of claim 1 , wherein at least one of R 1 and R 2 is alkyl, unsubstituted or substituted with halo-.

4. The pharmaceutical composition of claim 1 , wherein at least one of D and E is attached to an additional macrocycle-forming linker of the formula [-L 1 -S-L 2 -S-L 3 -].

5. The pharmaceutical composition 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.

6. The pharmaceutical composition of claim 1 , wherein the peptidomimetic macrocycle comprises an α-helix.

7. The pharmaceutical composition of claim 6 , wherein [-L 1 -S-L 2 -S-L 3 -] spans approximately 1, 2, 3, 4 or 5 turns of the α-helix.

8. The pharmaceutical composition of claim 6 , wherein the length of [-L 1 -S-L 2 -S-L 3 -] is about 5 Å to about 9 Å per turn of the α-helix.

9. The pharmaceutical composition of claim 6 , wherein the length of [-L 1 -S-L 2 -S-L 3 -] is approximately equal to the length of from about 5 carbon-carbon bonds to about 13 carbon-carbon bonds.

10. The pharmaceutical composition of claim 6 , wherein the macrocycle comprises a ring of about 17 atoms to 25 atoms or a ring of about 29 atoms to about 37 atoms.

11. The pharmaceutical composition of claim 1 , wherein x+y+z is at least 3.

12. The pharmaceutical composition of claim 1 , wherein L 2 is [R 4 —K—R 4 -]n.

13. The pharmaceutical composition of claim 12 , wherein R 4 is arylene.

14. The pharmaceutical composition of claim 13 , wherein K is CO.

15. The pharmaceutical composition of claim 14 , wherein R 4 is phenylene and n is 1.

16. The pharmaceutical composition of claim 15 , wherein L 1 and L 3 are alkylene.

17. The pharmaceutical composition of claim 15 , wherein L 1 and L 3 are methylene.

Assignees

• Aileron Therapeutics Inc

Inventors

• Nash Huw M

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61K38/12 Primary

  Cyclic peptides {, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C (A61K38/043 - A61K38/046 take precedence)} · CPC title

• C07K14/705

  Receptors; Cell surface antigens; Cell surface determinants {(tumour specific antigens C07K14/4748)} · CPC title

• C07K14/68

  Melanocyte-stimulating hormone [MSH] · CPC title