Proteolytically resistant hydrogen bond surrogate helices

Patent metadata

Field	Value
Publication number	US-9376469-B2
Application number	US-201213724887-A
Country	US
Kind code	B2
Filing date	Dec 21, 2012
Priority date	Dec 21, 2011
Publication date	Jun 28, 2016
Grant date	Jun 28, 2016

Abstract

The present invention relates to peptidomimetics having a stable, internally constrained protein secondary structure, where the peptidomimetics contain a hydrogen bond surrogate in the internal constraint, and at least one beta amino acid. Methods for promoting cell death using peptidomimetics that inhibit p53/hDM2 are also disclosed.

First claim

What is claimed:

1. A peptidomimetic having a stable, internally constrained protein secondary structure, wherein the peptidomimetic is a compound of Formula I:

wherein:
B is C(R 1 )(R 1′ ), O, S, or NR 1 ;
is a double bond and each R 1′ is absent; or is a single bond and each R 1′ is independently hydrogen, an amino acid side chain, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, or an arylalkyl;
each R 1 is independently hydrogen, an amino acid side chain, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, or an arylalkyl;
R 2 is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl; an alpha amino acid; a beta amino acid; a peptide; a targeting moiety; a tag; —OR 5 wherein R 5 is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; —(CH 2 ) 0-1 N(R 5 ) 2 wherein each R 5 is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; or a moiety of Formula A:

wherein:
R 2′ is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl; an alpha amino acid; a beta amino acid; a peptide; a targeting moiety; a tag; —OR 5 wherein R 5 is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; or —(CH 2 ) 0-1 N(R 5 ) 2 wherein each R 5 is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag;
m′ is zero or any number;
each b is independently one or two; and
c is one or two;

R 3 is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl; an alpha amino acid; a beta amino acid; a peptide; a targeting moiety; a tag; —OR 5 wherein R 5 is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; —N(R 5 ) 2 wherein each R 5 is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; or a moiety of Formula B:

wherein:
R 3′ is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl; an alpha amino acid; a beta amino acid; a peptide; a targeting moiety; a tag; —OR 5 wherein R 5 is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; or —N(R 5 ) 2 wherein each R 5 is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag;
m″ is zero or any number; and
each d is independently one or two;

each R 4 is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, or an arylalkyl;
m, n′, and n″ are each independently zero, one, two, three, or four, wherein the sum of m, n′, and n″ is from two to six;
m′″ is zero or one;
a is one or two;
each o is independently one or two;
p is one or two; and
wherein at least one of the following conditions is met
(i) m is one, two, three, or four and at least one o is two;
(ii) p is two;
(iii) m′″ is one and a is two;
(iv) R 2 is a beta amino acid;
(v) R 2 is a moiety of Formula A wherein m′ is at least one and at least one b is two;
(vi) R 2 is a moiety of Formula A wherein c is two;
(vii) R 2 is a moiety of Formula A wherein R 2′ is a beta amino acid;
(viii) R 3 is a beta amino acid;
(ix) R 3 is a moiety of Formula B wherein m″ is at least one and at least one d is two; and
(x) R 3 is a moiety of Formula B wherein R 3′ is a beta amino acid.

2. The peptidomimetic according to claim 1 , wherein B is C(R 1 )(R 1′ ).

3. The peptidomimetic according to claim 1 , wherein B is O.

4. The peptidomimetic according to claim 1 , wherein B is S.

5. The peptidomimetic according to claim 1 , wherein B is NR 1 .

6. The peptidomimetic according to claim 1 , wherein there are 9 to 12 atoms in the macrocycle portion of the compound.

7. The peptidomimetic according to claim 6 , wherein there are 11 atoms in the macrocycle portion of the compound.

8. The peptidomimetic according to claim 1 , wherein there are 12 to 15 atoms in the backbone of the macrocycle portion of the compound.

9. The peptidomimetic according to claim 8 , wherein there are 14 atoms in the backbone of the macrocycle portion of the compound.

10. The peptidomimetic according to claim 1 , wherein there are 15 to 18 atoms in the backbone of the macrocycle portion of the compound.

11. The peptidomimetic according to claim 10 , wherein there are 17 atoms in the backbone of the macrocycle portion of the compound.

12. The peptidomimetic according to claim 1 , wherein there are 20 to 24 atoms in the backbone of the macrocycle portion of the compound.

13. The peptidomimetic according to claim 12 , wherein there are 22 atoms in the backbone of the macrocycle portion of the compound.

14. The peptidomimetic according to claim 1 , wherein the peptidomimetic is a compound of Formula IA:

wherein:
is a double bond and R 1′ and R 4′ are both absent; or is a single bond and R 1′ is hydrogen, an amino acid side chain, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, or an arylalkyl and R 4′ is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, or an arylalkyl.

15. The peptidomimetic according to claim 1 , wherein the peptidomimetic is a compound of Formula IB:

16. The peptidomimetic according to claim 1 , wherein the peptidomimetic is a compound of Formula IC:

17. A peptidomimetic having a stable, internally constrained protein secondary structure, wherein the peptidomimetic is a compound of Formula IIA:

wherein:
each B is independently C(R 1 )(R 1′ ), O, S, or NR 1 ;
each is independently a single or double bond, wherein:
when is a double bond, the R 1′ and R 4′ associated therewith are both absent; and
when is a single bond, the R 1′ associated therewith is hydrogen, an amino acid side chain, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl,

Assignees

• Univ New York

Inventors

• Arora Paramjit S
• Patgiri Anupam
• Joy Stephen

Classifications

• A61K38/31

  Somatostatins · CPC title

• C07K2/00

  Peptides of undefined number of amino acids; Derivatives thereof · CPC title

• C07K7/50

  Cyclic peptides containing at least one abnormal peptide link · CPC title

• C07K7/56 Primary

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

• C07K7/54

  with at least one abnormal peptide link in the ring · CPC title