eIF2B Activator Compounds for Reducing Cellular ISR

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Solution Overview

Problem

There is no effective treatment for Amyotrophic Lateral Sclerosis (ALS) that can stop or reverse the progression of the disease, and existing treatments targeting the integrated stress response (ISR) have limitations in regulating protein homeostasis.

Innovation Solution

A compound is developed to significantly reduce the integrated stress response (ISR) and activate the activity of eIF2B, promoting normal protein synthesis in cells, potentially treating ALS and other neurodegenerative diseases.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If existing treatments targeting the integrated stress response (ISR) are used, then some regulatory effect is achieved, but the ability to effectively stop or reverse ALS progression is insufficient

Engineering Contradiction:

Improveeffectiveness of treatmentVSAvoidability to stop or reverse disease progression

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent modifies the chemical structure of elF2B activator compounds by changing parameters such as substituting specific hydrogen atoms with fluorine atoms (e.g., positions 3 and 5 of the pyridine ring), adding or removing functional groups, and adjusting molecular weight and lipophilicity. These parameter changes aim to enhance the compound's ability to activate elF2B and reduce ISR, thereby improving therapeutic effectiveness for ALS and other neurodegenerative diseases.

Inventive Principle:

Principle #35Parameter changes

2Stability of the object's composition

If the integrated stress response (ISR) is activated, then protein homeostasis regulation occurs, but cognitive defects and neurodegenerative disease progression are exacerbated

Engineering Contradiction:

Improveprotein homeostasisVSAvoidcognitive defects and disease progression

Core Design Contradiction:

Stability of the object's compositionVSObject-affected harmful factors

Solution Approach 1:

The patent uses elF2B activator compounds as intermediary substances that specifically target and activate elF2B enzyme. This activation serves as a mediator to restore protein translation and reduce ISR activation, thereby maintaining protein homeostasis while preventing the harmful effects of chronic ISR activation such as cognitive defects and neurodegenerative disease progression.

Inventive Principle:

Principle #24Intermediary (Mediator)

3Reliability

If elF2B activator compounds are developed to reduce ISR, then normal protein synthesis is promoted, but the complexity of drug development and clinical translation increases

Engineering Contradiction:

Improvenormal protein synthesisVSAvoiddrug development complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent performs preliminary actions by conducting extensive in vitro and in vivo screenings to identify and optimize elF2B activator compounds before clinical translation. This includes assessing compound potency, selectivity, and pharmacokinetic properties in advance, thereby reducing the complexity of subsequent clinical development and accelerating the path to therapeutic application.

Inventive Principle:

Principle #10Preliminary action

Data Source

PatentEP4624458A1Compound, pharmaceutical composition containing same, synthesis method therefor and use thereof

Publication Date: 2025.10.01 SHENZHEN ZHONGGE BIOLOGICAL TECH CO LTD

AI summary

The present application provides a compound as shown in formula (0), a pharmaceutical composition containing same, a synthesis method therefore and a use thereof. The compound of the present application can significantly reduce the integrated stress response (ISR) of cells and activate the activity of elF2B, so that the protein in the cells tends to be synthesized normally, providing more possible drugs for ISR pathway-mediated diseases or condition elF2B-related diseases, and/or diseases related to regulation of the activity or level of elF2B activity or level, and regulation of the activity or level of the elF2 pathway or ISR pathway.