Pyridine Macrocycle Compounds for ASK1 Inhibition
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Solution Overview
Problem
There is a need for new compounds that can inhibit Apoptosis Signal-regulating Kinase 1 (ASK1) to address its role in various diseases including neurodegenerative, cardiovascular, inflammatory, and metabolic disorders, as existing treatments are inadequate in modulating ASK1 activity effectively.
Innovation Solution
Development of specific compounds, represented by Formula (I), (II), and their pharmaceutically acceptable salts, which act as ASK1 inhibitors, capable of modulating ASK1 activity to treat disorders responsive to ASK1 inhibition.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing treatments are used, then current therapeutic approaches are maintained, but ASK1 activity cannot be effectively modulated
Solution Approach 1:
The patent develops novel pyridine macrocycle compounds with specific molecular structures (Formula I and II) that fundamentally change the chemical parameters of ASK1 inhibitors. These compounds introduce new structural features including pyridine rings, macrocyclic frameworks, and specific substituent patterns that enable effective ASK1 inhibition, thereby resolving the inability of existing treatments to modulate ASK1 activity
Solution Approach 2:
The invention creates composite molecular structures combining multiple functional moieties within a single compound framework. The compounds integrate pyridine rings, macrocyclic structures, and various substituent groups (R1-R6) to form complex molecules that simultaneously achieve binding affinity and selective inhibition of ASK1, overcoming the limitations of simpler existing treatments
2Reliability
If new ASK1 inhibitor compounds are developed, then therapeutic benefits for neurodegenerative and cardiovascular diseases are achieved, but compound structure complexity increases
Solution Approach 1:
The patent segments the inhibitor molecule into distinct functional regions: a core pyridine macrocycle structure, variable substituent positions (R1-R6), and linkers connecting to heteroaryl groups. This segmentation allows systematic optimization of different regions to achieve therapeutic efficacy while managing structural complexity through modular design
Solution Approach 2:
The invention applies local quality by introducing specific functional groups at defined positions within the macrocycle structure. Each substituent (R1-R6) and heteroaryl group is strategically placed to provide localized interactions with ASK1 binding sites, enabling precise inhibition while maintaining overall structural organization
Data Source
AI summary
Provided are compounds of Formula (I′), including compounds of Formulas (I), (II), (III), (IIIA) and (IIIB), wherein L, R1, R3 and n are as defined herein, and pharmaceutically acceptable salts thereof, and methods for their use and production. These compounds can be useful, e.g., in the treatment of disorders responsive to the inhibition of apoptosis signal-regulating kinase 1 (ASK1).