Imidazopyridine NURR1 Modulators for Potent Selective Activity
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Solution Overview
Problem
Current pharmacological agents for modulating Nurr1 activity are not sufficiently potent and specific, limiting their therapeutic potential in neurodegenerative diseases and inflammatory conditions.
Innovation Solution
Development of novel imidazopyridine compounds that act as potent Nurr1 modulators, either as agonists or inverse agonists, with enhanced potency and specificity for Nurr1 dimers, achieving EC50 or IC50 values of 1 µM or less.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing pharmacological agents are used to modulate Nurr1 activity, then some therapeutic effect is achieved, but the potency and specificity are insufficient
Solution Approach 1:
The patent applies parameter changes by systematically modifying molecular parameters of Nurr1 modulators, including introducing specific heterocyclic scaffolds (imidazopyridine, pyrimidinoquinoline), adjusting substituent positions, and optimizing molecular weight and lipophilicity parameters to achieve EC50 values of 1 µM or less while maintaining high specificity
Solution Approach 2:
The patent applies local quality by focusing structural modifications on specific local regions of the Nurr1 binding site, such as the chloroquinolin-4-amine fragment and imidazopyridine core, to enhance binding affinity and selectivity for Nurr1 dimers while minimizing off-target effects
2Reliability
If Nurr1 modulators are developed with enhanced potency, then therapeutic efficacy is improved, but compound complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the Nurr1 modulator molecule into functional segments: a core heterocyclic scaffold (imidazopyridine or pyrimidinoquinoline), specific substituent groups (chloro, methyl, hydroxyl), and pharmacophore elements that collectively achieve high potency while maintaining manageable structural complexity
Solution Approach 2:
The patent applies taking out by extracting and optimizing key functional fragments from complex natural ligands, such as isolating the chloroquinolin-4-amine fragment and imidazopyridine core structures that are responsible for Nurr1 binding, and using these simplified fragments as the basis for high-potency synthetic modulators
Data Source
Figure 1~1c
Figure 2~2e
AI summary
The present invention relates to novel imidazopyridine compounds as modulators of the transcription factor Nuclear receptor related 1 (Nurr1, NR4A2) in medicine, particularly in the prevention and/or treatment of a degenerative and/or inflammatory disease.