Peptidomimetic macrocycles

Patent metadata

Field	Value
Publication number	US-9175047-B2
Application number	US-201013129118-A
Country	US
Kind code	B2
Filing date	Jan 14, 2010
Priority date	Jan 14, 2009
Publication date	Nov 3, 2015
Grant date	Nov 3, 2015

Abstract

Peptidomimetic macrocycles and methods of using such macrocycles for the treatment of viral disease are described.

First claim

What is claimed is:

1. A peptidomimetic macrocycle-comprising a crosslinker linking the α-positions of at least two amino acids, and an amino acid sequence that is at least 80% identical to the amino acid sequence NleDVN$TLL$LKVAibAQ (SEQ ID NO: 113) and, wherein the peptidomimetic macrocycle has a structure 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, or

each 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, optionally substituted with R 5 ;
each L is independently a macrocycle-forming linker of the formula -L 1 -L 2 -;
each L 1 and L 2 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 independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;
each K is independently O, S, SO, SO 2 , CO, 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;
each R 7 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with a D residue;
each R 8 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with an E residue;
amino acids represented as $ are alpha-Me S5-pentenyl-alanine olefin amino acids;
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; and
each n is independently an integer from 1-5.

2. The peptidomimetic macrocycle of claim 1 , wherein the amino acid sequence of the peptidomimetic macrocycle is at least about 90% identical to the amino acids sequence NleDVN$TLL$LKVAibAQ (SEQ ID NO: 113).

3. The peptidomimetic macrocycle of claim 1 , wherein the peptidomimetic macrocycle comprises a helix.

4. The peptidomimetic macrocycle of claim 1 , wherein the peptidomimetic macrocycle comprises a 3 10 helix.

5. The peptidomimetic macrocycle of claim 1 , wherein the peptidomimetic macrocycle comprises an α,α-disubstituted amino acid.

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

7. The peptidomimetic macrocycle of claim 1 , wherein the peptidomimetic macrocycle comprises an alpha helix.

8. The peptidomimetic macrocycle of claim 1 , wherein R 1 is alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-.

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

Assignees

• Nash Huw M
• Annis David Allen
• Aileron Therapeutics Inc

Inventors

• Nash Huw M
• Annis David Allen

Classifications

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• C07K14/005 Primary

  from viruses · CPC title

• A61K38/10 Primary

  Peptides having 12 to 20 amino acids {(A61K38/043 - A61K38/046 take precedence)} · CPC title

• C12N2760/16022

  New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes · CPC title

• C07K7/56

  the cyclisation not occurring through 2,4-diamino-butanoic acid · CPC title