Fused Pyrimidine KCC2 Modulators for Neuronal Hyperexcitability

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Solution Overview

Problem

There is a need for new compounds that can activate KCC2 to treat neurological disorders such as epilepsy, neuropathic pain, Rett's syndrome, autism, mental disorders, and conditions with neuronal hyperexcitability, as existing treatments are inadequate.

Innovation Solution

Development of fused amino pyrimidine compounds and their pharmaceutically acceptable salts that selectively modulate KCC2, enhancing its expression or activity to restore GABA inhibition and treat neurological disorders.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If genetic modification or phosphorylation modulation is used to activate KCC2, then therapeutic effect is improved, but device complexity and ease of manufacture deteriorate

Engineering Contradiction:

Improvetherapeutic effectVSAvoidcomplexity of genetic modification

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent replaces complex genetic modification systems with small molecule compounds that can orally administer to modulate KCC2 activity. The fused pyrimidine compounds directly interact with KCC2 protein to enhance its function, substituting the need for genetic engineering approaches while achieving similar therapeutic effects in treating neurological disorders.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

Solution Approach 2:

The patent uses small molecule compounds with specific chemical structures (fused pyrimidine core with various substituents) that bind to and modulate KCC2 activity. By changing chemical parameters of the compounds, the patent optimizes KCC2 activation while maintaining ease of manufacture and administration compared to genetic approaches.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If KCC2 activity is increased to treat neurological disorders, then therapeutic benefit is improved, but manufacturing precision and ease of manufacture worsen

Engineering Contradiction:

Improvetherapeutic benefitVSAvoidprecision required for compound synthesis

Core Design Contradiction:

ReliabilityVSManufacturing precision

Solution Approach 1:

The patent divides the complex KCC2 modulation task into manageable synthetic steps, creating a series of substituted fused pyrimidine compounds with systematic variations. The modular chemical structure allows stepwise synthesis and optimization, making manufacturing more feasible while maintaining therapeutic efficacy.

Inventive Principle:

Principle #1Segmentation

3Adaptability or versatility

If new compounds are developed to activate KCC2, then adaptability to different neurological disorders is improved, but device complexity and development time worsen

Engineering Contradiction:

Improveadaptability to neurological disordersVSAvoidcomplexity of compound development

Core Design Contradiction:

Adaptability or versatilityVSDevice complexity

Solution Approach 1:

The patent develops a series of fused pyrimidine compounds with a common core structure that can treat multiple neurological disorders by activating KCC2. The universal mechanism of KCC2 activation across different conditions (epilepsy, neuropathic pain, other hyperexcitability disorders) allows one compound class to address multiple diseases, reducing the need for separate development programs.

Inventive Principle:

Principle #6Universality (Multi-functionality)

Data Source

PatentUS12617795B2Substituted 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidines, 5,7-dihydrofuro[3,4-d]pyrimidines, and pyrido[2,3-d]pyrimidines as KCC2 modulators

Publication Date: 2026.05.05 ASTRAZENECA AB

AI summary

The invention concerns compounds of Formula (I):or pharmaceutically acceptable salts thereof, wherein R1, R2, R7 and ring A have any of the meanings hereinbefore defined in the description; process for their preparation; pharmaceutical compositions containing them and their use in treating KCC2 mediated diseases.