Nitrogen-Containing Heterocyclic Compounds for Non-Covalent Nrf2 Activation

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Solution Overview

Problem

There is a need for a non-covalently binding type of Nrf2 activator that can reduce interaction with non-target proteins, as existing compounds like bardoxolone methyl pose a risk of heart failure due to covalent binding with non-target proteins.

Innovation Solution

A compound with a unique chemical structure, represented by formula (I), or its pharmacologically acceptable salt or solvate, effectively activates Nrf2 while minimizing interactions with non-target proteins.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If covalent binding compounds (e.g., bardoxolone methyl) are used as Nrf2 activators, then strong Nrf2 activation effect is achieved, but interaction with non-target proteins occurs causing heart failure risk

Engineering Contradiction:

ImproveNrf2 activation efficacyVSAvoidinteraction with non-target proteins

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent changes the binding mode parameter from covalent to non-covalent interaction. The compound of formula (I) is designed to activate Nrf2 through non-covalent binding, fundamentally altering the interaction mechanism to eliminate irreversible covalent modification of non-target proteins while preserving Nrf2 activation capability

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent introduces a non-covalent binding mechanism as an intermediary approach between complete covalent binding and no binding. This intermediate binding mode provides sufficient affinity for Nrf2 activation while avoiding the harmful permanent modification of non-target proteins associated with covalent bonding

Inventive Principle:

Principle #24Intermediary (Mediator)

2Object-affected harmful factors

If non-covalently binding Nrf2 activators are developed, then interaction with non-target proteins is reduced, but clinical development progress is limited

Engineering Contradiction:

Improveinteraction with non-target proteinsVSAvoidclinical development progress

Core Design Contradiction:

Object-affected harmful factorsVSProductivity

Solution Approach 1:

The patent segments the Nrf2 activator development into specific structural components represented by formula (I), with defined substituents (R1-R6, Y, Z) that can be independently optimized. This modular approach enables systematic structure-activity relationship studies to advance clinical development while maintaining non-covalent binding safety

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent creates composite molecular structures combining specific heterocyclic cores with various substituent groups in formula (I). This composite design allows optimization of both non-covalent binding specificity for Nrf2 and pharmacokinetic properties necessary for clinical development

Inventive Principle:

Principle #40Composite materials

Data Source

PatentUS12441735B2Nitrogen-containing heterocyclic compound having NRF2 activation effect

Publication Date: 2025.10.14 CHUGAI PHARMA CO LTD

AI summary

Provided is a low-molecular compound or a salt thereof, or a solvate thereof which has the ability to activate Nrf2.The present invention provides a compound represented by the formula (1) or a salt thereof, or a solvate thereof, wherein Xa1 is CRa1 or N, Xa3 is CRa3 or N, Ra1, Ra2 and Ra3 are each independently selected from the group consisting of hydrogen, halogen and C1-C6 alkoxy, Xb1, Xb2 and Xb3 are each independently selected from the group consisting of CH2, O, NH, S and C═O, Y is C6-C10 aryl optionally having a substituent or 5- to 10-membered heteroaryl optionally having a substituent, and Z is C6-C10 aryl optionally having a substituent, 5- to 10-membered heteroaryl optionally having a substituent or C1-C6 alkyl optionally having a substituent.