Selective Wild Type c-Kit Inhibitors With Low CNS Penetration
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Solution Overview
Problem
Current treatments for mast cell-mediated disorders such as chronic urticaria and asthma are inadequate, as they do not effectively target mast cells and often result in significant side effects due to non-selective inhibition of c-kit kinase.
Innovation Solution
Development of novel compounds that are selective inhibitors of wild type c-kit kinase, with minimal CNS penetration, to treat mast cell-associated diseases like chronic urticaria and asthma, offering improved efficacy and reduced side effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If non-selective inhibition of c-kit kinase is used to treat mast cell-mediated disorders, then mast cell activity is suppressed, but significant side effects occur due to inhibition of other kinases
Solution Approach 1:
The patent applies local quality by designing compounds with specific molecular structures (Formula I) that possess selective binding characteristics for wild type c-kit kinase over other kinases. The specific substitution patterns on the pyridine ring and heterocyclic groups create a unique binding profile that targets mast cell signaling pathways while sparing other kinase systems, thereby reducing side effects while maintaining therapeutic efficacy.
Solution Approach 2:
The patent employs parameter changes by systematically varying molecular parameters such as substituent types, ring sizes, and stereochemical configurations to optimize selectivity. By adjusting these structural parameters, the compounds achieve high specificity for wild type c-kit kinase, enabling effective treatment with minimal off-target effects.
2Reliability
If c-kit inhibition is used to treat chronic urticaria and asthma, then mast cell mediators are reduced, but CNS penetration causes additional side effects
Solution Approach 1:
The patent applies local quality by designing compounds with specific molecular structures (Formula I) that possess selective binding characteristics for wild type c-kit kinase over other kinases. The specific substitution patterns on the pyridine ring and heterocyclic groups create a unique binding profile that targets mast cell signaling pathways while sparing other kinase systems, thereby reducing side effects while maintaining therapeutic efficacy.
Solution Approach 2:
The patent uses the blood-brain barrier as an intermediary mechanism to prevent CNS penetration. The molecular structure of the compounds is designed to be sufficiently polar and bulky to be restricted by the blood-brain barrier, thereby preventing entry into the CNS and avoiding neurological side effects while maintaining peripheral efficacy.
3Ease of operation
If current mast cell treatments are used, then some symptom control is achieved, but insufficient therapeutic value due to multiple pro-inflammatory mediators
Solution Approach 1:
The patent applies segmentation by targeting the upstream c-kit kinase signaling pathway, which segments the complex mast cell mediator release process at its source. By inhibiting c-kit kinase, the compound prevents the activation of multiple pro-inflammatory mediators (histamines, leukotrienes, prostaglandins) simultaneously, providing comprehensive therapeutic value rather than addressing individual mediators separately.
Data Source
AI summary
Disclosed is a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof. The variables in Formula (I) are defined herein.Compounds of Formula (I) are useful for inhibiting wild type c-kit kinase and for treating disorders and diseases mediated by wild type c-kit kinase in humans or non-humans.