Discovery of an Achiral Small Molecule TREM2 Agonist with Improved Pharmacokinetic Profile and Validated Target Engagement.

The triggering receptor expressed on myeloid cells 2 (TREM2) is a lipid-sensing immunoreceptor on microglia that has emerged as a therapeutic target for Alzheimer's disease. Here, we report the discovery of , an achiral structural analog of -the first small molecule TREM2 agonist to enter clinical development. was synthesized via a modular and enantioselective-free route using sequential Suzuki couplings, enabling rapid scaffold diversification. Compared to , the stereochemically simplified derivative ( ) exhibits superior microglial phagocytosis and validated target engagement. induces TREM2 activation in HEK293-hTREM2/DAP12 cells, and its direct binding to TREM2 was confirmed using both microscale thermophoresis (MST) and surface plasmon resonance (SPR). Importantly, also demonstrates a superior pharmacokinetic profile to , including enhanced metabolic stability in human and mouse microsomes, favorable PAMPA permeability, and a LogD . compatible with CNS penetration. Docking studies suggested a potential binding mode of at the extracellular domain of TREM2, revealing key polar and hydrophobic interactions. These findings position as a synthetically accessible and pharmacokinetically favorable lead for the development of TREM2-targeted therapies.