Design, synthesis and evaluation of dual modulators targeting glutaminyl cyclase and cannabinoid CB2 receptor

Alzheimer's disease (AD) is the major cause of dementia and one of the most common chronic diseases affecting aging populations. As such, novel and effective therapeutic agents are urgently needed to address this growing public health challenge. Given the involvement of glutaminyl cyclase (QC) and cannabinoid type 2 receptor (CB2R) dysregulation in AD progression, we designed, synthesized, and evaluated a series of biphenyl carboxamide derivatives as dual modulators targeting QC and CB2R. In vitro assays showed that most of the 35 compounds exhibited notable QC inhibitory and CB2R agonistic activity; for example, compound 18 demonstrated potent activity against both targets (QC, IC₅₀ = 0.65 ± 0.07 μM; CB2R, EC₅₀ = 0.32 ± 0.04 μM). Structure-activity relationship analysis indicated that the amide-linked motif (R¹) is critical for CB2R agonistic potency, while the introduction of a methoxy group (R²) on the biphenyl scaffold enhances activity against both targets. Molecular docking further supported the interactions between these compounds and their respective protein targets. Taken together, these dual modulators targeting QC and CB2R warrant further investigation as potential therapeutic candidates for AD.