Macrocyclic Nitrogen Crown Ether Kinase Inhibitors with Improved Solubility

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Solution Overview

Problem

Existing protein kinase inhibitors lack sufficient enzyme inhibition activity and water solubility, leading to unsatisfactory clinical outcomes and adverse effects.

Innovation Solution

Development of macrocyclic nitrogen-containing crown ether compounds, represented by formula (I), which exhibit good inhibitory activity against protein kinases like LRRK2, JAK1, JAK2, JAK3, EGFR, and CDK9, with improved water solubility.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If existing protein kinase inhibitors are used, then enzyme inhibition activity is achieved, but water solubility is insufficient

Engineering Contradiction:

Improveenzyme inhibition activityVSAvoidwater solubility

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The patent modifies the chemical structure parameters of protein kinase inhibitors by introducing macrocyclic nitrogen-containing crown ether groups with specific substituents (R1-R6), changing the molecular properties to achieve both high enzyme inhibition activity and improved water solubility simultaneously

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention creates composite molecular structures combining macrocyclic crown ether frameworks with various functional groups (aromatic rings, heterocycles, alkyl chains), forming hybrid compounds that exhibit enhanced solubility while maintaining or improving kinase inhibition efficacy

Inventive Principle:

Principle #40Composite materials

2Ease of operation

If existing protein kinase inhibitors are used, then clinical treatment is provided, but adverse effects occur

Engineering Contradiction:

Improveclinical treatment efficacyVSAvoidadverse effects

Core Design Contradiction:

Ease of operationVSObject-generated harmful factors

Solution Approach 1:

The patent introduces specific local functional groups (R1-R6 substituents) at different positions of the macrocyclic framework, optimizing local interactions with target kinases to enhance therapeutic efficacy while reducing off-target effects and adverse reactions

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The invention converts the potential harm of poor solubility (which causes precipitation and reduced bioavailability) into a benefit by designing hydrophilic macrocyclic structures that improve water solubility, thereby enhancing drug delivery and reducing toxic effects from poor dissolution

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

Data Source

PatentEP4592286A1Macrocyclic nitrogen-containing crown ether compound and use thereof as protein kinase inhibitor

Publication Date: 2025.07.30 ARTIVILA BIOPHARMA

AI summary

The present invention provides a macrocyclic nitrogen-containing crown ether compound represented by formula (I) and use thereof as a protein kinase inhibitor.