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Article Abstract
The microglial lipid-sensing receptor TREM2 is a promising therapeutic target for Alzheimer's disease. We report the discovery of , a racemic structural analog of the clinical-stage TREM2 agonist . Synthesized via a concise, modular, and enantioselective-free route using sequential Suzuki couplings, enables rapid scaffold diversification. Compared to , this stereochemically simplified derivative exhibits superior microglial phagocytosis and activates TREM2 signaling in HEK293-hTREM2/DAP12 cells, demonstrating validated target engagement. Direct binding of to TREM2 was unequivocally confirmed by both surface plasmon resonance (SPR) and microscale thermophoresis (MST). Critically, displays a superior in vitro pharmacokinetic profile to : enhanced metabolic stability in human and mouse liver microsomes, favorable passive permeability (PAMPA), and a CNS-compatible log D.. Docking studies suggest a potential binding mode for within TREM2's extracellular domain, revealing key interactions. These attributes establish as an accessible and pharmacokinetically favorable lead compound with strong potential for developing TREM2-targeted therapies.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC12359007 | PMC |
| http://dx.doi.org/10.1021/acsmedchemlett.5c00299 | DOI Listing |
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