Control of hypoxia-inducible gene expression with oligooxopiperazine nonpeptidic helix mimetics

Patent metadata

Field	Value
Publication number	US-9783526-B2
Application number	US-201615018130-A
Country	US
Kind code	B2
Filing date	Feb 8, 2016
Priority date	Feb 16, 2012
Publication date	Oct 10, 2017
Grant date	Oct 10, 2017

Abstract

The present invention relates to oligooxopiperazines that mimic helix αB of the C-terminal transactivation domain of HIF-1α. Also disclosed are pharmaceutical compositions containing these oligooxopiperazines and methods of using these oligooxopiperazines (e.g., to reduce gene transcription, treat or prevent disorders mediated by interaction of HIF-1α with CREB-binding protein and/or p300, reduce or prevent angiogenesis in a tissue, induce apoptosis, and decrease cell survival and/or proliferation).

First claim

What is claimed is:

1. An oligooxopiperazine of Formula I:

wherein:
each of R 1 , R 2 , R 3 , and R 4 is independently an amino acid side chain, H, N(R) 2 , OR, halogen, an alkyl, or an aryl; wherein each R is independently H, an alkyl, or an aryl;
each R 6 is independently H, N(R) 2 , OR, halogen, an alkyl, or an aryl; wherein each R is independently H, an alkyl, or an aryl;
A is X 1 or C, wherein:
X 1 is H, COR′, CO 2 R′, CONHR′, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a protecting group for protection of an amine, a targeting moiety, or a tag; wherein R′ is H, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag; and
C is a moiety of the formula

wherein:
each X′ is independently H, COR′, CO 2 R′, CONHR′, N(R″) 2 , an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag; wherein:
R′ is H, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag; and
each R″ is independently H, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag;
R 0 is an amino acid side chain, H, N(R) 2 , OR, halogen, an alkyl, or an aryl; wherein each R is independently H, an alkyl, or an aryl; and
R 6 is H, N(R) 2 , OR, halogen, an alkyl, or an aryl; wherein each R is independently H, an alkyl, or an aryl; and
B is OR′, COR′, N(R′″) 2 , an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a protecting group for protection of a carboxylic acid, a targeting moiety, or a tag;
wherein:
R′ is H, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag; and
each R′″ is independently H, CO 2 R′, CONHR′, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag;

and wherein:
(i) A is X 1 , R 1 and R 2 are hydrophobic and R 4 is a hydrogen bond acceptor or hydrogen bond donor, with the proviso that at least one of the following conditions is not met: R 1 is a leucine side chain, R 2 is a leucine side chain, and R 4 is a glutamine side chain;
(ii) A is a moiety of formula

R 0 and R 3 are hydrophobic, and R 4 is a hydrogen bond acceptor or hydrogen bond donor, with the proviso that at least one of the following conditions is not met: R 1 is a leucine side chain, R 2 is a leucine side chain, and R 4 is a glutamine side chain, and with the proviso that the compound is not a compound of formula

where X is H, COCH 3 , or any amino acid, and Y is OH, NH 2 , OMe, or any amino acid;
(iii) the oligooxopiperazine is BB2-125; or
(iv) the oligooxopiperazine is BB2-164.

2. The oligooxopiperazine according to claim 1 , wherein A is X 1 , R 1 and R 2 are hydrophobic, and R 4 is a hydrogen bond acceptor or hydrogen bond donor.

3. The oligooxopiperazine according to claim 1 , wherein A is a moiety of formula

R 0 and R 3 are hydrophobic, and R 4 is a hydrogen bond acceptor or hydrogen bond donor.

4. The oligooxopiperazine according to claim 1 , wherein the oligooxopiperazine is BB2-164.

5. A pharmaceutical formulation comprising:
an oligooxopiperazine according to claim 1 and
a pharmaceutically acceptable vehicle.

6. The pharmaceutical formulation according to claim 5 , wherein A is X 1 , R 1 and R 2 are hydrophobic, and R 4 is a hydrogen bond acceptor or hydrogen bond donor.

7. The pharmaceutical formulation according to claim 5 , wherein A is a moiety of formula

R 0 and R 3 are hydrophobic, and R 4 is a hydrogen bond acceptor or hydrogen bond donor.

8. The pharmaceutical formulation according to claim 5 , wherein the oligooxopiperazine is BB2-164.

9. The oligooxopiperazine according to claim 1 , wherein:
(i) when A is X 1 , X 1 is H, COR′, CO 2 R′, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a protecting group for protection of an amine, a targeting moiety, or a tag; wherein R′ is H, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag;
(ii) when A is C, each X′ is independently H, COR′, CO 2 R′, N(R″) 2 , an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag; wherein:
R′ is H, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag; and
each R″ is independently H, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag; and

(iii) when B is N(R′″) 2 , each R′″ is independently H, CO 2 R′, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag.

10. An oligooxopiperazine, wherein the oligooxopiperazine is BB2-125.

11. A pharmaceutical formulation comprising:
the oligooxopiperazine of claim 10 and
a pharmaceutically acceptable vehicle.

Assignees

• Univ New York

Inventors

• Arora Paramjit S
• Lao Brooke Bullock

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P7/06

  Antianaemics · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title