Hydrogen-bond surrogate peptides and peptidomimetics for p53 reactivation

Patent metadata

Field	Value
Publication number	US-9605026-B2
Application number	US-201414160001-A
Country	US
Kind code	B2
Filing date	Jan 21, 2014
Priority date	Jan 19, 2013
Publication date	Mar 28, 2017
Grant date	Mar 28, 2017

Abstract

The present invention relates to peptidomimetics for reactivating p53. Methods of using the peptidomimetics are also disclosed.

First claim

What is claimed:

1. A peptidomimetic, wherein the peptidomimetic is selected from the group consisting of:
(i) a compound of Formula Ia, Ib, Ic, Id, Ie, or If:

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; and
wherein:
(a) at least one R 1 at the positions labeled “Glu” is a glutamic acid side chain,
(b) at least one R 1 at the positions labeled “Leu” is a leucine side chain,
(c) at least one R 1 at the positions labeled “Ala” is an alanine side chain,
(d) at least one R 1 at the positions labeled “Arg” is an arginine side chain,
(e) at least one R 1 at the positions labeled “Asp” is an aspartic acid side chain, and
(f) at least one R 1 at the positions labeled “Gln” is a glutamine side chain;

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:

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;
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:

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;
each R 4 is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, or an arylalkyl;
R 4′ is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, or a double bond between C(R 4′ ,R 4 ) and B;
a is one or two;
each b is independently one or two;
c is one or two;
each d is independently one or two;
m′ is zero or any number;
m″ is zero or any number;
n′ and n″ are each independently zero, one, two, three, or four;
each o is independently one or two; and
p is one or two;

(ii) a compound of Formula IIa, IIb, IIc, IId, or, IIe:

wherein:
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; and
wherein:
(a) at least one R 1 at the positions labeled “Glu” is a glutamic acid side chain,
(b) at least one R 1 at the positions labeled “Leu” is a leucine side chain,
(c) at least one R 1 at the positions labeled “Ala” is an alanine side chain,
(d) at least one R 1 at the positions labeled “Arg” is an arginine side chain,
(e) at least one R 1 at the positions labeled “Asp” is an aspartic acid side chain, and
(f) at least one R 1 at the positions labeled “Gln” is a glutamine side chain;

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:

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;
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:

R 3′ is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl

Assignees

• Univ New York
• Univ Ohio State Res Found
• Univ Michigan Regents

Inventors

• Arora Paramjit S
• Pan Quintin
• Mapp Anna

Classifications

• A61K33/24

  Heavy metals; Compounds thereof · CPC title

• 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

• C07K7/56

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

• C07K7/64 Primary

  Cyclic peptides containing only normal peptide links · CPC title

• A61K38/08

  Peptides having 5 to 11 amino acids {(A61K38/043 - A61K38/046 take precedence)} · CPC title