Formula I Modulators of Integrated Stress Response Pathway

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Solution Overview

Problem

There is a continuing need for new compounds with improved pharmacokinetic properties as modulators of the integrated stress response pathway to effectively treat diseases related to integrated stress response, which current modulators may not adequately address due to limitations in activity, solubility, selectivity, and side effects.

Innovation Solution

Development of specific compounds of formula (I) or their pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers, which are designed to modulate the integrated stress response pathway, potentially offering enhanced activity, solubility, selectivity, and reduced side effects.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current modulators of the integrated stress response pathway are used, then the pathway can be modulated to treat diseases, but the pharmacokinetic properties are insufficient leading to limited activity, solubility, and selectivity

Engineering Contradiction:

Improvedisease treatment effectivenessVSAvoidpharmacokinetic properties

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent applies parameter changes by systematically modifying chemical structure parameters of the modulator compounds. The core structure features variable substituents (R1-R6, X1-X1a, A1-A2) that can be tuned to optimize pharmacokinetic properties including solubility, metabolic stability, and target selectivity while maintaining ISR pathway modulation activity

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent employs composite molecular structures combining heterocyclic cores with various functional groups and substituents. This composite approach creates molecules with optimized pharmacokinetic profiles by integrating different structural elements that contribute collectively to solubility, permeability, and target binding affinity

Inventive Principle:

Principle #40Composite materials

2Reliability

If current modulators are used to modulate the integrated stress response pathway, then disease treatment is possible, but side effects are increased due to insufficient selectivity

Engineering Contradiction:

Improvetherapeutic benefitVSAvoidside effects

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent applies local quality by introducing specific substituents at particular positions on the core structure (R1-R6 at different ring positions, X1 and X1a at specific linkage points). Each local structural modification is designed to enhance selectivity for the intended ISR pathway target while minimizing off-target effects that cause side effects

Inventive Principle:

Principle #3Local quality

Data Source

PatentUS20230125481A1Modulators of the integrated stress response pathway

Publication Date: 2023.04.27 EVOTECH INT GMBH

AI summary

The present invention relates to compounds of formula (I) or pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers thereof, wherein R1, R2, R2a, R3, Ra1, Ra2, Ra4, Ra5, X1, X1a, A1 and A2 have the meaning as indicated in the description and claims. The invention further relates to pharmaceutical compositions comprising said compounds, their use as medicament and in a method for treating and preventing of one or more diseases or disorders associated with integrated stress response.