Selective Hydroxamates for Nav1.7/Nav1.8 Pain Channel Blockade
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Solution Overview
Problem
Current treatments for neuropathic pain lack specificity and efficacy, leading to adverse effects due to non-selective blockage of voltage-gated sodium channels, particularly Nav 1.7 and Nav 1.8, which are key in pain transmission.
Innovation Solution
Development of hydroxamates that selectively block Nav 1.7 and/or Nav 1.8 channels to mitigate pain-related pathologies, offering compositions, kits, and treatment methods.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If non-selective voltage-gated sodium channel blockers are used to treat neuropathic pain, then pain relief is achieved, but adverse effects increase due to non-specific blockage of multiple channel subtypes
Solution Approach 1:
The invention segments the broad class of voltage-gated sodium channels into specific subtypes (Nav1.7 and Nav1.8) and develops compounds that selectively target these particular subtypes. The hydroxamate compounds of Formula (I) are designed to discriminate between different Nav channel subtypes, blocking only Nav1.7 and/or Nav1.8 while sparing other subtypes involved in normal physiological functions, thereby achieving pain relief with reduced adverse effects
Solution Approach 2:
The invention applies local quality by creating compounds with selective affinity for specific Nav channel subtypes expressed in nociceptive neurons. The hydroxamate structure with specific substituent patterns (R1-R20 groups) provides localized molecular interactions that confer selectivity for Nav1.7 and Nav1.8 channels in pain pathways, rather than uniformly blocking all sodium channels throughout the body
2Reliability
If current first-line treatments (opioid analgesics, local anesthetics, anticonvulsants, antidepressants) are used for neuropathic pain, then some pain control is achieved, but low efficacy and adverse effects limit their use
Solution Approach 1:
The invention extracts the therapeutic effect from the class of sodium channel blockers and isolates it to a specific mechanism: selective blockade of Nav1.7 and Nav1.8 channels. By taking out only the pain-relieving action associated with these specific subtypes and separating it from the adverse effects caused by non-selective blockade, the invention creates a treatment that maintains efficacy while improving safety and acceptability
Solution Approach 2:
The invention changes the selectivity parameter of sodium channel blockers by developing compounds with specific molecular structures (Formula (I) hydroxamates) that exhibit preferential binding to Nav1.7 and Nav1.8 channels. This parameter change from non-selective to selective blockade transforms the therapeutic profile, maintaining pain control while reducing the adverse effects that limit current treatment options
Data Source
AI summary
The present invention relates to Nav 1.7 and/or Nav 1.8 blocking hydroxamates. More specifically, the present invention is related to hydroxamates comprising the Formula (I), in which the substituents R1 to R10, as well as their derivatives R11 to R20, are selected independently of the groups defined in the specification, as well as their preparation processes, compositions comprising at least one of these compounds, uses, treatment methods to treat or prevent pain-related pathologies and kits. The present invention belongs to the fields of medicinal chemistry, organic synthesis, as well as the treatment of pain-related diseases.