TREM2 Modulator Compounds Addressing Receptor Loss of Function
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Solution Overview
Problem
There is a high unmet medical need for modulators of Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) to address neurodegenerative diseases such as Alzheimer's disease, Frontotemporal lobar degeneration, Parkinson's disease, Huntington disease, Nasu-Hakola disease, Multiple sclerosis, Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathies, Charcot-Marie-Tooth disease, and Amyotrophic lateral sclerosis.
Innovation Solution
Development of compounds that modulate TREM2 activity, specifically represented by Formula (I) compounds and their pharmaceutically acceptable salts, which can be used to treat conditions associated with loss-of-function of TREM2.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If TREM2 activity is not modulated, then neurodegenerative diseases progress due to TREM2 deficiency, but existing treatments do not effectively address the underlying pathogenesis
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of TREM2 ligands to create compounds with optimized binding affinity and modulatory activity. By systematically varying molecular parameters (substituents, functional groups, stereochemistry) in the compounds of Formula (I), the invention achieves enhanced ability to modulate TREM2 activity, thereby improving therapeutic effectiveness for neurodegenerative diseases associated with TREM2 deficiency
Solution Approach 2:
The patent uses small molecule compounds as intermediaries to bridge the gap between TREM2 deficiency and therapeutic intervention. These compounds act as mediators that bind to TREM2 and restore its signaling function, effectively translating chemical structure into biological activity. The compounds serve as intermediary agents that activate TREM2 pathways without requiring genetic modification, thus addressing the unmet medical need for TREM2 modulators
2Reliability
If TREM2 ligands are used to activate TREM2, then microglial function is enhanced, but specificity and selectivity of modulation must be maintained
Solution Approach 1:
The patent applies local quality by introducing specific substituent patterns at particular positions of the core molecular structure. Different substituents (R1-R6) are placed at specific locations to fine-tune the compound's interaction with TREM2, ensuring selective activation of desired microglial responses while avoiding off-target effects. This localized structural optimization enables precise control over modulation specificity
Solution Approach 2:
The patent incorporates dynamic elements through stereoisomerism and conformational flexibility in the compound design. The ability of the molecules to adopt different conformations and the use of specific stereoisomers (e.g., (R)- and (S)-enantiomers) allow the compounds to dynamically interact with TREM2, enhancing binding affinity and selectivity. This dynamic interaction ensures specific microglial activation while maintaining modulation precision
Data Source
AI summary
The present invention relates to compounds useful for modulating Triggering Receptor Expressed on Myeloid Cells-2 (“TREM2”). The invention also relates to the compounds for use in treatment of conditions related to loss of function of TREM2, such as neurodegenerative diseases, and to pharmaceutical compositions comprising the compounds.