Fused Ring P2X4 Antagonists With Selectivity and Metabolic Stability
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Solution Overview
Problem
There is a lack of effective P2X4 antagonists for treating chronic cough and other diseases, with existing compounds showing insufficient activity, selectivity, and metabolic stability.
Innovation Solution
Development of fused ring compounds with high P2X4 antagonistic activity, good selectivity, and low toxicity, represented by a specific chemical formula incorporating various substituents and functional groups.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing P2X4 antagonist compounds are used, then some level of receptor inhibition is achieved, but the activity, selectivity, and metabolic stability are insufficient
Solution Approach 1:
The patent systematically modifies chemical parameters including substituting different groups at positions R1, R2, R3, and varying the heteroatom composition of rings A and B to optimize the balance between P2X4 antagonistic activity, selectivity, and metabolic stability. This involves changing electronic properties, steric effects, and metabolic susceptibility through controlled parameter variation
Solution Approach 2:
The invention creates composite molecular structures combining a core fused ring system (isoquinoline or quinoline) with various substituent groups and heterocyclic rings. This composite approach allows integration of multiple functional properties: the core provides receptor binding, while substituents and heterocyclic rings contribute to selectivity and metabolic stability
2Reliability
If molecular structure complexity is increased to improve selectivity, then selectivity is enhanced, but synthesis difficulty and manufacturing complexity increase
Solution Approach 1:
The molecular structure is divided into distinct functional segments: a core fused ring system, substituent groups at defined positions, and heterocyclic rings A and B. This segmentation allows independent optimization of each segment for selectivity while maintaining modular synthesis approaches that manage manufacturing complexity
Solution Approach 2:
The core fused ring structure serves multiple functions simultaneously: providing the basic scaffold for P2X4 receptor binding, enabling attachment of diverse substituents for selectivity optimization, and facilitating various heterocyclic ring combinations. This multi-functionality reduces the need for completely different molecular frameworks
Data Source
AI summary
Disclosed is a fused ring compound and an application thereof. Disclosed is a fused ring compound represented by formula I, a pharmaceutically acceptable salt, a stereoisomer, a tautomer, an isotope compound, a crystal form, a nitrogen oxide, a solvate, or a solvate of the pharmaceutically acceptable salt thereof. The fused ring compound of the present invention has high P2X4 antagonistic activity, excellent selectivity, low toxicity and excellent metabolic stability.