Nrf2-Activating Heterocyclic Crystals With Non-Covalent Keap1 Binding
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Solution Overview
Problem
Existing Nrf2 activators covalently bind to Keap1, posing a risk of interaction with non-target proteins and potential heart failure, necessitating a non-covalently binding type of Nrf2 activator to reduce such interactions.
Innovation Solution
Development of crystals of nitrogen-containing heterocyclic compounds represented by specific formulas, or their salts or solvates, which exhibit excellent Nrf2-activating effects and minimize interactions with non-target proteins.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If covalent binding Nrf2 activators are used, then Nrf2 activation effect is achieved, but interaction with non-target proteins occurs causing potential heart failure
Solution Approach 1:
The patent changes the binding mechanism parameter from covalent to non-covalent interaction. The compound of formula (1) is designed to activate Nrf2 through non-covalent binding to Keap1, fundamentally altering the interaction type to eliminate irreversible covalent modification while maintaining therapeutic efficacy. This parameter change resolves the contradiction by preserving Nrf2 activation while avoiding harmful non-target protein interactions associated with covalent binding.
Solution Approach 2:
The patent introduces a specific compound structure (formula (1)) as an intermediary that mediates Nrf2 activation through non-covalent interaction with Keap1. This intermediary approach allows selective activation of the Nrf2 pathway without the harsh covalent binding mechanism, thereby achieving the desired therapeutic effect while minimizing off-target effects and potential cardiotoxicity.
2Object-affected harmful factors
If non-covalently binding Nrf2 activators are developed, then interaction with non-target proteins is reduced, but clinical development has not yet been achieved
Solution Approach 1:
The patent segments the Nrf2 activator development into specific chemical series (formula (1) and its salts/solvates) with defined structural characteristics. By segmenting the compound space into this specific series, the patent provides a focused, clinically viable candidate that overcomes the general limitation of non-covalent binders lacking clinical approval. The segmentation allows for optimized pharmacological properties while maintaining non-covalent binding safety profile.
Solution Approach 2:
The patent creates a new compound series (formula (1)) that copies the successful Nrf2 activation mechanism of existing drugs but implements it through non-covalent binding instead of covalent binding. This copying approach adapts the proven therapeutic strategy to a safer binding mode, enabling clinical development potential that previous non-covalent inhibitors lacked.
3Reliability
If covalent binding to Keap1 is used, then Nrf2 activation is achieved, but risk of heart failure increases
Solution Approach 1:
The patent fundamentally changes the binding parameter from covalent to non-covalent interaction. The compound of formula (1) activates Nrf2 through reversible non-covalent binding to Keap1, eliminating the irreversible nature of covalent bonds that lead to prolonged off-target effects and cardiotoxicity. This parameter change maintains therapeutic efficacy while reducing heart failure risk.
Solution Approach 2:
The patent converts the potential harm of strong binding into a benefit by using non-covalent interactions that are sufficiently strong to activate Nrf2 but weak enough to avoid irreversible off-target effects. The reversible nature of non-covalent binding allows the compound to exert therapeutic effect while naturally limiting exposure time to non-target proteins, thereby converting what could be harmful persistent binding into a safe, transient interaction.
Data Source
Figure 1
Figure 2(A)~2(B)
Figure 3
AI summary
Provided is a low-molecular compound or a salt thereof, or a solvate thereof which has a Nrf2-activating effect. The present invention provides a crystal of a compound represented by any of the following formulas (1) to (5) or a salt thereof, or a solvate thereof: