Selective Ion Channel Modulators Avoiding MAO Inhibition
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Solution Overview
Problem
Current medicaments that modulate sodium and/or calcium channels for treating neurological, psychiatric, inflammatory, urogenital, and gastrointestinal diseases often exhibit monoamine oxidase (MAO) inhibitory activity, leading to adverse side effects such as hypertensive crises and serotoninergic syndrome, especially when combined with other drugs or consumed with tyramine-rich foods.
Innovation Solution
Development of 2-[2-(phenyl)ethylamino]alkaneamide derivatives that act as selective sodium and/or calcium channel modulators, substantially free from MAO inhibitory activity, reducing the risk of these side effects by avoiding MAO inhibition and thus providing a safer therapeutic option for these pathologies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current medicaments that modulate sodium and/or calcium channels are used, then therapeutic efficacy for neurological, psychiatric, inflammatory, urogenital, and gastrointestinal diseases is achieved, but MAO inhibitory activity causes adverse side effects such as hypertensive crises and serotoninergic syndrome
Solution Approach 1:
The patent segments the pharmacological activity into two distinct components: sodium/calcium channel modulation (therapeutic effect) and MAO inhibition (side effect source). By designing compounds that selectively target voltage-gated sodium and/or calcium channels without significant MAO inhibitory activity, the invention separates the desired therapeutic action from the harmful side effects, achieving reliable treatment efficacy while eliminating MAO-related adverse reactions
Solution Approach 2:
The invention applies local quality by creating compounds with selective affinity for specific ion channel subtypes (e.g., Nav1.7, Nav1.8, Cav2.2) while maintaining lack of affinity for MAO enzymes. This localized specificity ensures that the medicament exerts its therapeutic effect only at the intended molecular target (sodium/calcium channels) without affecting other systems (MAO), thereby achieving reliable therapy without MAO inhibitory side effects
2Adaptability or versatility
If MAO inhibitory activity is present in sodium and/or calcium channel modulators, then broad therapeutic coverage is achieved, but the risk of hypertensive crises and serotoninergic syndrome increases
Solution Approach 1:
The invention extracts and removes the MAO inhibitory activity component from the medicament while retaining the sodium/calcium channel modulation capability. By designing compounds that lack MAO inhibitory activity but maintain ion channel modulating effects, the patent eliminates the source of hypertensive crises and serotoninergic syndrome while preserving broad therapeutic coverage for multiple disease indications
Solution Approach 2:
The invention converts the historical limitation (MAO inhibition causing side effects) into a benefit by deliberately designing compounds that avoid MAO inhibition. This approach transforms what was previously a harmful dual-action profile into a beneficial selective-action profile, where the absence of MAO inhibition becomes the key advantage that enables safe and effective treatment across multiple therapeutic areas
Data Source
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AI summary
Substituted 2-[2-(phenyl)ethylamino]alkaneamide derivatives of formula (I) wherein X, Y, Z, R, R1, R2, R3, R'3, R4, R5, R6, R7 have the meanings defined in the specification and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them as active ingredient and their use as sodium and/or calcium channel modulators useful in preventing, alleviating and curing a wide range of pathologies, including, but not limited to, neurological, cognitive, psychiatric, inflammatory, urogenital and gastrointestinal diseases, where the above mechanisms have been described as playing a pathological role.