Kv7 Channel Activator Compositions With Kv7.2/7.3 Selectivity
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Solution Overview
Problem
Existing Kv7 channel modulators, such as retigabine, exhibit complex and concentration-dependent effects on neuronal Kv7 channels, leading to unclear implications for neuronal responsiveness and systems physiology, and lack specificity for the Kv7.2/7.3 heteromultimer over Kv7.4 homomultimer, potentially causing untoward side effects.
Innovation Solution
Development of compounds that are potent and biased towards the Kv7.2/7.3 heteromultimer, with improved specificity and reduced side effects compared to retigabine, characterized by enhanced Kv7 channel activation and reduced voltage-dependence.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If retigabine is used as a Kv7 channel opener, then channel current is increased, but specificity for Kv7.2/7.3 heteromultimer over Kv7.4 homomultimer is poor leading to untoward side effects
Solution Approach 1:
The patent applies local quality by designing compounds with specific molecular structures (Formula 1 and Formula 2) that are tailored to interact preferentially with the Kv7.2/7.3 heteromultimer binding site. The compounds contain specific structural features including a heteroaryl ring system, substituent patterns, and stereochemical configurations that create localized interactions with the Kv7.2/7.3 interface, thereby achieving high specificity for this particular channel subtype while minimizing off-target effects on other Kv7 channels.
2Reliability
If Kv7 channel openers are used to treat neurological disorders, then neuronal excitability is reduced, but the complex and concentration-dependent effects create unclear implications for systems physiology
Solution Approach 1:
The patent applies parameter changes by optimizing the compounds' potency parameters (EC50 values in the nanomolar to low micromolar range) and their voltage-dependence characteristics. The compounds are designed to activate Kv7 channels at physiological membrane potentials with a specific shift in the voltage activation curve, creating a predictable and controllable effect on neuronal excitability that is less concentration-dependent than previous openers. This allows for more reliable therapeutic effects with a narrower therapeutic window.
Data Source
AI summary
Provided herein are optionally substituted benzoimidazol-1,2-yl amides, pharmaceutical compositions comprising a therapeutically effective amount of such compounds and a pharmaceutically acceptable excipient, and methods of treating Kv7 associated diseases, such as, epilepsy, amyotrophic lateral sclerosis, various types of pain, hyperexcitability, a dyskinesia, dystonia, mania and tinnitus with such compounds and pharmaceutical compositions.