ISR Pathway Modulators With 1,3-Dioxane Derivatives
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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 such as cancer and neurodegenerative disorders.
Innovation Solution
Development of a new class of 1,3-dioxane derivatives as modulators of the integrated stress response pathway, characterized by specific substituents and functional groups that enhance activity, solubility, selectivity, and reduce side effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional chemotherapy or radiation therapy is used to treat cancer, then tumor growth may be inhibited, but severe side effects occur including damage to healthy cells and organs
Solution Approach 1:
The patent applies local quality by making the chemotherapy agent responsive to specific local conditions (low pH and/or high reactive oxygen species) in the tumor microenvironment. The agent remains inactive in healthy tissues with normal pH and ROS levels, then activates locally within the tumor to exert cytotoxic effects, thereby achieving cancer treatment efficacy while minimizing damage to healthy cells
Solution Approach 2:
The patent utilizes parameter changes by designing the chemotherapy agent to undergo chemical transformation in response to changes in the tumor microenvironment parameters (pH and ROS levels). The agent transitions from an inactive state in normal conditions to an active cytotoxic state when exposed to the altered parameters (lower pH and/or higher ROS) characteristic of tumor tissue, enabling selective activation at the target site
2Reliability
If high doses of chemotherapy agents are administered to improve treatment efficacy, then tumor response may be enhanced, but toxicity to healthy tissues increases
Solution Approach 1:
The patent introduces the tumor microenvironment parameters (low pH and/or high ROS) as intermediaries that mediate between the administered chemotherapy agent and the tumor cells. These intermediaries serve as triggers that activate the prodrug specifically within the tumor, converting it from an inactive state to an active cytotoxic state, thereby enabling effective tumor treatment without requiring high systemic doses that would harm healthy tissues
Solution Approach 2:
The patent extracts the activation function from the systemic circulation and localizes it to the tumor microenvironment. By designing the agent to remain inactive during circulation and only activate when encountering the specific conditions (low pH and/or high ROS) of the tumor, the harmful activation effect is extracted from healthy tissues and confined to the tumor site, reducing systemic toxicity while maintaining treatment efficacy
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, Ra1, Ra2, Ra3, Ra4, Ra5, Ra6, 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.