Small-Molecule TNF Alpha Modulators for Reduced Cardiac Toxicity

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Solution Overview

Problem

Current treatments for inflammatory and autoimmune disorders, neurological and neurodegenerative disorders, pain and nociceptive disorders, cardiovascular disorders, metabolic disorders, ocular disorders, and oncological disorders lack potent small molecule modulators of TNF alpha activity.

Innovation Solution

Development of compounds of Formula (I) or their pharmaceutically acceptable salts, solvates, or stereoisomers, which can modulate TNF alpha activity for the treatment of these disorders.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If macromolecular TNF alpha inhibitors (anti-TNF alpha antibodies and soluble TNF alpha receptor fusion proteins) are used, then TNF alpha binding inhibition is achieved, but molecular size and complexity increase

Engineering Contradiction:

ImproveTNF alpha binding inhibitionVSAvoidmolecular complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent changes the molecular size parameter from macromolecular (antibodies and fusion proteins) to small molecule compounds, while maintaining the functional parameter of TNF alpha binding inhibition through structure-activity relationship optimization

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention extracts the essential binding function from complex macromolecular structures and implements it through simplified small molecule compounds that retain TNF alpha modulatory activity without the bulk of protein structures

Inventive Principle:

Principle #2Taking out (Extraction)

2Reliability

If benzimidazole core compounds are used, then TNF alpha modulation is achieved, but cardiac toxicity and reduced cell permeability occur

Engineering Contradiction:

ImproveTNF alpha modulationVSAvoidcardiac toxicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent modifies specific local regions of the benzimidazole core structure through substituent variations and structural optimizations, creating compounds with improved safety profiles while retaining TNF alpha modulatory activity at the target site

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The invention converts the potentially harmful cardiac toxicity of benzimidazole compounds into a benefit by optimizing the structure to reduce off-target effects while enhancing selective TNF alpha modulation, thereby transforming a toxic compound class into a safe therapeutic agent

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

3Reliability

If benzimidazole core compounds are used, then TNF alpha modulation is achieved, but cell permeability is reduced

Engineering Contradiction:

ImproveTNF alpha modulationVSAvoidcell permeability

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

The patent changes the physicochemical parameters of the benzimidazole compounds, including lipophilicity, molecular weight, and hydrogen bonding capacity, to optimize cell membrane permeability while preserving TNF alpha binding affinity

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention segments the benzimidazole molecule into distinct functional regions (pharmacophore, linker, and substituent groups) that can be independently optimized for permeability without compromising the essential binding interactions

Inventive Principle:

Principle #1Segmentation

Data Source

PatentUS12410179B2Modulators of TNF alpha activity and uses thereof

Publication Date: 2025.09.09 RAYTHERA INC

AI summary

Described herein are modulators of TNF alpha activity and pharmaceutical compositions comprising said inhibitors. The subject compounds and compositions are useful for the treatment of TNF alpha-mediated disorders or diseases.