Pyrazolone Derivatives Stabilizing HIF Proteins for Ischemia Treatment

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Solution Overview

Problem

Current therapies lack effective activators for the HIF transcription factor, which is crucial for responding to hypoxia and ischemia, limiting the treatment options for related disorders.

Innovation Solution

Development of new derivatives of substituted dihydropyrazolones that stabilize HIF1α and HIF2α proteins, allowing them to activate target genes, specifically designed to mimic natural stabilizing agents like insulin and growth factors.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If HIF1α protein is expressed under normal oxygen conditions, then it is rapidly degraded by the ubiquitin-proteasome system, but this prevents activation of hypoxia-responsive genes when oxygen is available

Engineering Contradiction:

ImproveHIF1α degradation controlVSAvoidgene activation efficiency

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent employs prolyl hydroxylase enzymes to hydroxylate specific proline residues on HIF1α, changing its chemical state. This hydroxylation modifies the protein's properties, enabling pVHL binding and subsequent degradation by the ubiquitin-proteasome system, thus controlling HIF1α levels based on oxygen availability

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent introduces pVHL as an intermediary protein that mediates the degradation of hydroxylated HIF1α. pVHL acts as a bridge between the hydroxylated HIF1α and the ubiquitin-proteasome system, facilitating controlled degradation and preventing inappropriate gene activation under normoxic conditions

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If HIF1α is stabilized by hypoxia or growth factors, then it can activate target genes, but this mechanism is not sufficient for therapeutic intervention in ischemic conditions

Engineering Contradiction:

ImproveHIF1α stabilizationVSAvoidtherapeutic applicability

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent develops small molecule compounds that copy or mimic the stabilizing effect of natural agents like insulin and growth factors on HIF1α. These compounds replicate the biological function of endogenous stabilizers, enabling HIF1α accumulation and activation without requiring actual hypoxia or growth factor presence, thus providing therapeutic versatility

Inventive Principle:

Principle #26Copying

Solution Approach 2:

The patent creates compounds with broad therapeutic applicability that can stabilize HIF1α across multiple pathological conditions including ischemia, hypoxia, and inflammatory diseases. The compounds serve multiple functions: stabilizing HIF1α, promoting its nuclear translocation, and activating target genes relevant to various ischemic and hypoxic disorders

Inventive Principle:

Principle #6Universality (Multi-functionality)

3Ease of manufacture

If pyrazole derivatives are used for cardiovascular and hematological disorders, then existing treatments are available, but effective HIF activators for ischemic conditions are still lacking

Engineering Contradiction:

Improvecompound availabilityVSAvoidHIF activation efficacy

Core Design Contradiction:

Ease of manufactureVSReliability

Solution Approach 1:

The patent modifies the pyrazole derivative structure by introducing specific substituents and functional groups that enhance HIF stabilization activity. The chemical parameters of the molecules are optimized to improve their ability to prevent HIF1α degradation, transforming them from general cardiovascular agents into effective HIF activators for ischemic conditions

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent creates composite molecular structures combining pyrazole cores with various aromatic and heterocyclic groups. These composite structures integrate the pharmacological properties of pyrazoles with additional functional moieties that specifically target HIF stabilization, achieving both manufacturability and enhanced therapeutic efficacy

Inventive Principle:

Principle #40Composite materials

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

These compounds effectively stabilize HIF proteins, enabling their nuclear translocation and activation of hypoxia-responsive genes, providing a therapeutic potential for conditions associated with hypoxia and ischemia.

Implementation Method 1

These compounds are stabilizers of the HIF1α and/or HIF2α proteins

Methodology Applied

Scientific EffectProtein stabilization:

Implementation Method 2

enabling their nuclear translocation and activation of target genes

Methodology Applied

Scientific EffectNuclear translocation:

Data Source

PatentEP2382205B1Derivatives of 2-pyridin-2-yl-pyrazol-3(2H)-one, preparation and therapeutic use thereof as hif activators

Publication Date: 2014.04.23 SANOFI SA(FR)

AI summary

The invention relates to compounds according to the formula (I): R is a -SO2-NR3R4 group, a hydrogen atom, a halogen atom, a -halogeno(C1-C5)alkyl group, a -CO2R5 group or a -SO2-R4 group; R1 is a heterocycloalkyl group containing no nitrogen atoms, a -W-(C3-C6)cycloalkyl group, a -W-aryl group, a -W-heteroaryl group, a -W-heterocycloalkyl group, a -W-COOR5 group, a -W-CONR5R6 group; R2 is a hydrogen atom, a -(C1-C5)alkyl group, a -(C1-C5)alkylene-0-(C1-C5)alkyl group, a -halogeno(C1-C5)alkyl group, a -W-COOR5 group, a -W-C(O)NHR5 group or a -W-C(O)-NR5R6 group; n is 0, 1 or 2; W is a -(C1-C5)alkylene- group- or a -(C3-C6)cycloalkylene- group; R3 and R4, identical or different, are, independently from one another, a hydrogen atom, a -(C1-C5)alkyl group, a -(C3-C6)cycloalkyl group, a -(C1-C5)alkylene-O-(C1-C5)alkyl group, an aryl, a -CH2-aryl group, a heteroaryl, a heterocycloalkyl, a -W-OH group, a -W-CHOH-CH2OH group, a -W-CO2R5 group, a -W-NR5R6 group or a -W-O-(CH2)n-aryl group; or else R3 and R4 jointly form a heterocycloalkyl group with the nitrogen atom that supports them; R5 and R6, identical or different, are, independently from one another, a hydrogen atom, a -(C1-C5)alkyl group or a (C1-C5)halogenoalkyl group, as well as to a method for preparing same and to the therapeutic applications thereof.