ISR Modulator Compounds With Better Solubility and Selectivity
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Solution Overview
Problem
There is a need for new compounds that can effectively modulate the integrated stress response pathway with improved pharmacokinetic properties for the treatment of related diseases, including cancer and neurodegenerative disorders, while minimizing side effects and enhancing selectivity and solubility.
Innovation Solution
Development of a new class of compounds, represented by formula (I), which include specific substituents and functional groups, such as phenyl or aromatic heterocyclyl, to modulate the integrated stress response pathway, potentially stabilizing eIF2B and reducing phosphorylated eIF2alpha levels, thereby inhibiting ISR signaling.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing ISR modulators are used, then ISR signaling can be inhibited, but pharmacokinetic properties (solubility, selectivity, stability) are insufficient
Solution Approach 1:
The patent systematically modifies molecular parameters of ISR modulators by introducing specific substituents (R1-R6 groups) and functional groups to optimize physicochemical properties while maintaining biological activity. This includes adjusting lipophilicity, hydrogen bonding capacity, and molecular weight to improve solubility and pharmacokinetic profile.
Solution Approach 2:
The invention creates composite molecular structures combining core ISR modulating scaffolds with various functional moieties (carboxylic acid groups, hydroxyl groups, aromatic substituents) to achieve both therapeutic efficacy and improved pharmacokinetic properties simultaneously.
2Productivity
If ISR signaling is inhibited to treat cancer, then tumor growth is suppressed, but side effects increase
Solution Approach 1:
The patent introduces selective binding groups and substituents that enable preferential interaction with ISR pathway components in cancer cells while minimizing off-target effects. The molecular structure is optimized to achieve high affinity for eIF2B or eIF2alpha with reduced cross-reactivity with other cellular targets.
Solution Approach 2:
The compounds act as selective intermediaries that specifically modulate the ISR pathway without broadly suppressing all cellular functions. The molecular structure serves as a precise mediator to inhibit eIF2B-mediated translation initiation while preserving other critical cellular processes.
3Reliability
If eIF2B is stabilized to reduce phosphorylated eIF2alpha, then ISR signaling is inhibited, but compound complexity increases
Solution Approach 1:
The patent divides the molecular structure into distinct functional segments: core scaffold, substituent groups (R1-R6), and functional moieties. This segmentation allows independent optimization of each component to achieve ISR modulation with manageable structural complexity and facilitates systematic synthesis.
Data Source
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, R4, R4a, R4b, R4c, R4d, R4e, R5, R6 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 or preventing of one or more diseases or disorders associated with integrated stress response.