Selective Peptidomimetic Modulators for Cav2.2 Channel Pain Relief

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Solution Overview

Problem

Current treatments for chronic pain, such as Ziconotide, gabapentin, and pregabalin, have limitations including invasive administration, narrow therapeutic windows, and significant side effects, highlighting the need for novel selective modulators of CaV2.2 voltage-gated calcium channels that can effectively manage pain without adverse effects.

Innovation Solution

Development of compounds, including those represented by Formulas (I), (II), (III), and (IV), which are peptidomimetic modulators that target the Cav2.2 channel by disrupting the Cav2.2-CRMP2 interaction, thereby reducing calcium influx and pain, with specific structural features allowing for selective recognition and binding to the Cav2.2 channel.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If Ziconotide is used to block Cav2.2 channels, then pain relief is achieved, but invasive administration and significant side effects occur

Engineering Contradiction:

Improvepain relief efficacyVSAvoidside effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The invention changes the chemical structure parameters from peptide-based (Ziconotide) to small molecule peptidomimetics, altering pharmacokinetic properties to achieve oral bioavailability and reduced side effects while maintaining Cav2.2 channel blocking efficacy

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention creates simplified copies of the CBD3 peptide structure, retaining the essential pharmacophore features (basic amino acid residues for channel binding) while eliminating the need for invasive administration and reducing immunogenicity

Inventive Principle:

Principle #26Copying

2Reliability

If gabapentinoids are used to disrupt Cav2.2-α2δ-1 interaction, then pain management is achieved, but low efficacy and serious side effects occur

Engineering Contradiction:

Improvepain management efficacyVSAvoidside effects

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The invention extracts and targets the Cav2.2 channel directly, bypassing the α2δ-1 auxiliary subunit target of gabapentinoids, thereby achieving higher efficacy and avoiding side effects associated with indirect modulation

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

Instead of targeting the auxiliary subunit (gabapentinoid approach), the invention inverts the strategy to directly target the main Cav2.2 channel pore, achieving superior pain management with better safety profile

Inventive Principle:

Principle #13The other way round (Inversion)

3Reliability

If CBD3 peptide is used to interfere with Cav2.2-CRMP2 interaction, then calcium influx is reduced, but peptide stability and oral bioavailability are limited

Engineering Contradiction:

Improvecalcium influx inhibitionVSAvoidpeptide stability

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

The invention creates small molecule copies of the CBD3 peptide that replicate its binding pharmacophore (basic residues interacting with channel) while achieving the stability and bioavailability of small molecules

Inventive Principle:

Principle #26Copying

Solution Approach 2:

The invention substitutes the peptide-based interaction system with a small molecule chemical system, replacing the limitations of peptide stability with the advantages of small molecule pharmacokinetics while maintaining the same binding mechanism

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

Data Source

PatentUS20250017940A1Selective peptidomimetic modulators of cav2.2 (n-type) voltage-gated calcium channels and uses thereof

Publication Date: 2025.01.16 UNIV OF PITTSBURGH OF THE COMMONWEALTH SYST OF HIGHER EDUCATION

AI summary

The present invention relates to compounds of Formula (I):where R1, R2, X, s, and p are as defined herein. The present invention also relates to compounds of Formula (II), Formula (III), and:where R1a, R1b, R1d, R2a, R2b, R3b, X, Z, Z1, Z2, s, and p are as defined herein. Methods of using these compounds to regulate Cav2.2.target double-stranded RNA and to treat diseases and disorders, e.g., chronic pain, are also disclosed.