Phthalazine P2X3 Antagonists With Reduced Taste Side Effects

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Solution Overview

Problem

There is a need for novel phthalazine derivatives that selectively inhibit P2X3 receptors to treat respiratory diseases such as chronic cough and asthma, while minimizing side effects on taste function.

Innovation Solution

Development of phthalazine derivatives with specific structural features, including (5-6 membered)-heteroaryl and aryl groups, which act as selective P2X3 antagonists, reducing adverse effects on taste by preferentially targeting P2X3 receptors over P2X2/3 receptors.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If P2X3 receptor inhibition is achieved to treat respiratory diseases, then therapeutic efficacy is improved, but side effects on taste function occur due to P2X2/3 receptor inhibition

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidside effects on taste function

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by designing the phthalazine derivative with specific substituent patterns (R1, R2, R3 groups at defined positions) that create localized interactions with the P2X3 receptor binding site. This selective structural configuration enables preferential binding to P2X3 over P2X2/3, achieving high inhibition potency (IC50 values in nanomolar range) while minimizing off-target effects on taste function.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs parameter changes by systematically varying chemical parameters of the phthalazine core structure, including different heteroaryl groups (pyridinyl, pyrimidinyl, thiazolyl), alkyl substituents, and positional isomers. These parameter modifications optimize the balance between P2X3 binding affinity and selectivity, with compounds showing 10-100 fold selectivity ratios for P2X3 versus P2X2/3 receptors.

Inventive Principle:

Principle #35Parameter changes

2Object-affected harmful factors

If selective P2X3 antagonists are developed to avoid taste side effects, then side effect profile is improved, but structural complexity increases

Engineering Contradiction:

Improveside effect profileVSAvoidstructural complexity

Core Design Contradiction:

Object-affected harmful factorsVSDevice complexity

Solution Approach 1:

The patent applies segmentation by dividing the molecule into distinct functional modules: a core phthalazine scaffold providing P2X3 binding capability, and variable substituent groups (R1, R2, R3) that fine-tune selectivity and pharmacokinetic properties. This modular approach allows systematic optimization of selectivity while maintaining reasonable structural complexity for drug development.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent uses composite materials by combining the phthalazine heterocyclic core with diverse aromatic and heteroaromatic substituents (pyridine, pyrimidine, thiazole rings, alkyl groups). This composite molecular structure creates specific three-dimensional binding geometries that enhance P2X3 selectivity while keeping each component relatively simple and synthesizable.

Inventive Principle:

Principle #40Composite materials

Data Source

PatentUS12534455B2Phthalazine derivatives as P2X<sub>3 </sub>inhibitors

Publication Date: 2026.01.27 CHIESI FARMACEUTICI SPA

AI summary

The present invention relates to compounds of formula (I) inhibiting P2X purinoceptor 3; particularly the invention relates to compounds that are phthalazine derivatives, methods of preparing such compounds, pharmaceutical compositions containing them and therapeutic use thereof. The compounds of the invention may be useful in the treatment of many disorders associated with P2X3 receptors mechanisms, such as respiratory diseases including cough, asthma, idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD).