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

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