Design, synthesis and biological evaluation of suramin-derived dual antagonists of the proinflammatory G protein-coupled receptors P2Y2 and GPR17

Dual- or multi-target drugs are particularly promising for the treatment of complex diseases such as (neuro)inflammatory disorders. In the present study, we identified dual antagonists for two related pro-inflammatory G protein-coupled receptors (GPCRs), the purinergic receptor P2Y₂ receptor, and the orphan receptor GPR17. Based on the lead compound suramin small molecules were designed, synthesized, and modified, including benzenesulfonate, benzenesulfonamide, dibenzamide and diphenylurea derivatives. Structure-activity relationship studies identified 3-nitrophenyl 4-benzamidobenzenesulfonic acid derivatives as dual P2Y₂R/GPR17 antagonists. In particular, 3-nitrophenyl 4-(4-chlorobenzamido)benzenesulfonate (14l, IC₅₀ 3.01 μM at P2Y₂R, and 3.37 μM at GPR17) and 3-nitrophenyl-4-(2-chlorobenzamido)benzenesulfonate (14m, IC₅₀ 3.17 μM at P2Y₂R, and 1.67 μM at GPR17) exhibited dual antagonistic activity. Compound 14l was shown to act as an allosteric antagonist at both receptors. In addition, GPR17-selective antagonists were identified including 3-nitrophenyl 4-benzamidobenzenesulfonate (14a, IC₅₀ 3.20 μM) and 3-nitrophenyl 4-(3-(trifluoromethyl)benzamido)benzenesulfonate (14f, IC₅₀ 3.88 μM). The developed antagonists were selective versus other closely related P2Y receptors. They were found to possess high chemical and metabolic stability in human liver microsomes and therefore present good starting points for developing potent multi-target drugs with potential applications in inflammatory diseases.