Synthesis and Structural-Activity Relationship Analysis of 7-Deazaadenosine-Based BTK Inhibitors as Potent Antiplatelet Agents

Targeting glycoprotein VI (GPVI) signaling via Bruton’s tyrosine kinase (BTK) inhibition represents a promising antiplatelet strategy with minimized bleeding risk. We developed a novel series of 5′-modified 7-substituted 7-deazaadenosine derivatives as irreversible BTK inhibitors. Structure–activity relationship studies identified that the 4-phenoxyphenyl moiety at the 7-position effectively occupied the hydrophobic pocket, while flexible electrophilic warheads, particularly 2-chloroacetamide, at the 5′-position enhanced both covalent BTK inhibition and antiplatelet activity. Notably, the α-lyxo configuration provided superior cellular target engagement over conventional β-ribo counterparts. The lead compound 19b (L-α-lyxo, 5′-chloroacetamide) exhibited exceptional BTK inhibitory potency (IC 50 = 6 nM) and potent inhibition of collagen-induced platelet aggregation (IC 50 = 16 nM). Targeting GPVI signaling via BTK inhibition represents a promising antiplatelet strategy with the potential to reduce bleeding liability. These findings establish 19b as a promising lead compound for the development of GPVI-BTK pathway-targeted antiplatelet agents with a potentially improved bleeding profile.