ASK1 Inhibitors for NASH Treatment via Segmentation
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Solution Overview
Problem
There is a significant unmet need for novel therapeutic agents to treat nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease (NAFLD), as current treatments are inadequate and NASH can progress to cirrhosis and hepatocellular carcinoma.
Innovation Solution
Development of novel compounds, specifically 1-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)imidazolidin-4-one and their pharmaceutically acceptable salts, which act as inhibitors of apoptosis signal-regulating kinase 1 (ASK1) to intervene in liver diseases such as NAFLD and NASH.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If novel ASK1 inhibitor compounds are developed, then treatment options for NASH and NAFLD are improved, but the complexity of drug development and validation is increased
Solution Approach 1:
The patent divides the broad NASH treatment challenge into specific molecular targets (ASK1 kinase) and structures the compound library systematically around a core scaffold with variable substituents, making the complex development process more manageable through modular design
Solution Approach 2:
The patent systematically varies chemical parameters (substituents at positions A and B, heteroatom types, chain lengths) to generate a series of compounds with potentially different activities and profiles, allowing optimization without starting from scratch
2Reliability
If ASK1 inhibition is achieved, then disease progression is halted, but the risk of off-target effects and toxicity increases
Solution Approach 1:
The patent introduces heteroatoms (O, N, S) at specific positions in the molecule to create local regions of high binding affinity for ASK1, while simultaneously placing substituents that reduce off-target binding, achieving selective inhibition
Solution Approach 2:
The patent uses a core imidazolidinone scaffold as an intermediary structure that provides the basic binding interface for ASK1, while allowing attachment of functional groups that modulate specificity and reduce harmful off-target effects
3Ease of manufacture
If compound synthesis is simplified, then manufacturing cost is reduced, but the diversity of active compounds is limited
Solution Approach 1:
The patent separates the molecule into a core scaffold and detachable substituent groups (A and B positions), allowing the core to be synthesized once and then combined with different building blocks to create diverse compounds, reducing overall synthesis complexity
Solution Approach 2:
The patent designs a universal core structure (imidazolidin-4-one with pyridine-triazole substituent) that can serve as a platform for multiple active compounds by varying the A and B substituents, achieving diversity through a single master template
Data Source
AI summary
The present invention relates to inhibitors of apoptosis signal-regulating kinase 1 (“ASK1”), a process for synthesis of the compounds of the present invention, composition comprising the compounds and use of the compounds for inhibition of ASK1.