Selective Persistent Sodium Current Antagonists for Neurological Disorders

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Solution Overview

Problem

Current treatments for neurological disorders associated with aberrant persistent sodium currents are inadequate, as existing sodium channel blockers have severe side effects and lack selectivity, failing to effectively target persistent sodium currents without impacting transient currents.

Innovation Solution

Development of selective persistent sodium current antagonists with at least 20-fold selectivity for persistent sodium currents, administered to treat conditions like neuropathies, ischemias, and neurodegenerative diseases, using compounds represented by specific structural formulas that selectively inhibit persistent sodium channels without affecting transient channels.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If non-selective sodium channel blockers are used to treat neurological disorders, then persistent sodium currents are reduced, but transient sodium currents are also blocked causing paralysis and cardiac arrest

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidside effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent segments the sodium channel blocking function into two distinct selective actions: blocking persistent sodium currents while preserving transient sodium currents. This is achieved through compounds with specific molecular structures (Formulas 1-4) that exhibit differential binding affinity to persistent versus transient channel states, allowing therapeutic effect without harmful side effects

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The invention applies local quality by creating compounds with specific structural features (substituted phenyl, thienyl, pyridyl groups at defined positions) that confer selective affinity for persistent sodium channels. The molecular architecture is locally optimized at specific positions (R1-R7 substituents) to achieve state-dependent binding without affecting transient channels

Inventive Principle:

Principle #3Local quality

2Reliability

If existing sodium channel modulators are used, then some neurological symptoms are alleviated, but selectivity for persistent currents is insufficient leading to systemic effects

Engineering Contradiction:

Improvetherapeutic effectVSAvoidselectivity

Core Design Contradiction:

ReliabilityVSMeasurement precision

Solution Approach 1:

The patent changes the selectivity parameter by designing compounds with specific molecular properties (aromatic ring systems, substituent patterns, molecular weight 200-500 Da) that shift the binding equilibrium toward persistent channels. The selectivity ratio is optimized to at least 10-fold preference for persistent over transient currents through systematic variation of R1-R7 substituents

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS8124612B2Treating neurological disorders using selective antagonists of persistent sodium current

Publication Date: 2012.02.28 ALLERGAN INC

AI summary

The present invention provides methods of treating neurological disorders in a mammal by administering to the mammal an effective amount of a selective persistent sodium channel antagonist that has at least 20-fold selectivity for persistent sodium current relative to transient sodium current.