Phenylethylamino Derivatives as Selective Ion Channel Modulators
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Solution Overview
Problem
Current medications that modulate sodium and calcium channels for treating neurological, psychiatric, cardiovascular, inflammatory, ophthalmic, and gastrointestinal diseases often exhibit significant MAO inhibitory activity, leading to adverse side effects such as hypertensive crises and serotoninergic syndrome, especially when combined with other drugs like opioids or tricyclic antidepressants.
Innovation Solution
Development of phenylethylamino derivatives that act as selective sodium and/or calcium channel modulators with substantially reduced or no MAO inhibitory activity, minimizing side effects by avoiding the accumulation of monoamine transmitters and thus reducing the risk of adverse interactions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current medications modulate sodium and calcium channels for treating neurological, psychiatric, cardiovascular, inflammatory, ophthalmic, and gastrointestinal diseases, then therapeutic efficacy is improved, but MAO inhibitory activity increases leading to adverse side effects such as hypertensive crises and serotoninergic syndrome
Solution Approach 1:
The patent modifies the chemical structure of phenylethylamino derivatives by changing specific parameters (substituents on the phenyl ring, length of alkyl chains, position of functional groups) to alter the pharmacological profile. This allows the compounds to maintain sodium and calcium channel modulating activity while reducing or eliminating MAO inhibitory activity, thereby resolving the contradiction between therapeutic efficacy and harmful MAO inhibition effects
2Object-affected harmful factors
If phenylethylamino derivatives are developed as selective sodium and/or calcium channel modulators with reduced MAO inhibitory activity, then side effects are minimized, but development complexity increases
Solution Approach 1:
The patent divides the phenylethylamino derivative structure into distinct functional segments: a phenyl ring with specific substituents, an ethylamino chain, and a carboxamide group. By systematically varying these segmented components, the invention achieves selective channel modulation with reduced MAO inhibition, managing development complexity through structured molecular design
Solution Approach 2:
The patent introduces specific local modifications at different positions of the molecular structure (e.g., fluorine atoms at specific positions on the phenyl ring, different alkyl chain lengths) to locally optimize the compound's interaction with sodium and calcium channels while avoiding MAO inhibition sites, thereby reducing side effects without proportionally increasing overall development complexity
Data Source
AI summary
2-Phenylethylamino substituted carboxamide derivatives of formula (I); wherein J, W, R, R0 R1, R2, R3, and R4 have the meanings as 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 neurological, psychiatric, cardiovascular, inflammatory, ophthalmic, urology, and gastrointestinal diseases where the above mechanisms have been described as playing a pathological role, are described.