Discovery of a Small Molecule TREM2 Agonist with Improved In Vitro Pharmacokinetic Profile and Validated Target Engagement

The microglial lipid-sensing receptor TREM2 is a promising therapeutic target for Alzheimer’s disease. We report the discovery of C1, a racemic structural analog of the clinical-stage TREM2 agonist VG-3927. Synthesized via a concise, modular, and enantioselective-free route using sequential Suzuki couplings, C1 enables rapid scaffold diversification. Compared to VG-3927, this stereochemically simplified derivative exhibits superior microglial phagocytosis and activates TREM2 signaling in HEK293-hTREM2/DAP12 cells, demonstrating validated target engagement. Direct binding of C1 to TREM2 was unequivocally confirmed by both surface plasmon resonance (SPR) and microscale thermophoresis (MST). Critically, C1 displays a superior in vitro pharmacokinetic profile to VG-3927: enhanced metabolic stability in human and mouse liver microsomes, favorable passive permeability (PAMPA), and a CNS-compatible log D7.4. Docking studies suggest a potential binding mode for C1 within TREM2’s extracellular domain, revealing key interactions. These attributes establish C1 as an accessible and pharmacokinetically favorable lead compound with strong potential for developing TREM2-targeted therapies.