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

Patent metadata

Field	Value
Publication number	US-2016297802-A1
Application number	US-201615018130-A
Country	US
Kind code	A1
Filing date	Feb 8, 2016
Priority date	Feb 16, 2012
Publication date	Oct 13, 2016
Grant date	—

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

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;

wherein R 1 and R 2 are hydrophobic and R 4 is a hydrogen bond acceptor or hydrogen bond donor, or 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; and
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.

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

3 . (canceled)

4 . 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.

5 . The oligooxopiperazine according to claim 2 , wherein the oligooxopiperazine is BB2-164.

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

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

8 . (canceled)

9 . The pharmaceutical formulation according to claim 6 , 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.

10 . The pharmaceutical formulation according to claim 9 , wherein the oligooxopiperazine is BB2-164.

11 - 20 . (canceled)

21 . 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.

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

23 . A pharmaceutical formulation comprising:
the oligooxopiperazine of claim 22 and a pharmaceutically acceptable vehicle.

Assignees

• Arora Paramjit S
• Olenyuk Bogdan Z
• Lao Brooke Bullock
• Grishagin Ivan
• Univ New York
• Univ Southern California

Inventors

• Arora Paramjit S
• Olenyuk Bogdan Z
• Lao Brooke Bullock
• Grishagin Ivan

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

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

• A61P9/12

  Antihypertensives · CPC title

• A61P7/06

  Antianaemics · CPC title