Design, synthesis and biological evaluation of suramin-derived dual antagonists of the proinflammatory G protein-coupled receptors P2Y 2 and GPR17

• Published in: European journal of medicinal chemistry Vol. 186; p. 111789
• Main Authors: Pillaiyar, Thanigaimalai, Funke, Mario, Al-Hroub, Haneen, Weyler, Stefanie, Ivanova, Sabrina, Schlegel, Jonathan, Abdelrahman, Aliaa, Müller, Christa E
• Format: Journal Article
• Language: English
• Published: France 15.01.2020
• Subjects: Animals; CHO Cells; Cricetulus; Dose-Response Relationship, Drug; Drug Design; Humans; Microsomes, Liver - chemistry; Microsomes, Liver - metabolism; Molecular Structure; Receptors, G-Protein-Coupled - antagonists & inhibitors; Receptors, G-Protein-Coupled - metabolism; Receptors, Purinergic P2Y2 - metabolism; Structure-Activity Relationship; Suramin - chemical synthesis; Suramin - chemistry; Suramin - pharmacology; Dual antagonists; Multi-target drugs; GPR17; Suramin; P2Y receptor; Small molecules; Inflammatory diseases
• ISSN: 1768-3254

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 P2Y 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 P2Y R/GPR17 antagonists. In particular, 3-nitrophenyl 4-(4-chlorobenzamido)benzenesulfonate (14l, IC 3.01 μM at P2Y R, and 3.37  μM at GPR17) and 3-nitrophenyl-4-(2-chlorobenzamido)benzenesulfonate (14m, IC 3.17 μM at P2Y R, 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, IC 3.20 μM) and 3-nitrophenyl 4-(3-(trifluoromethyl)benzamido)benzenesulfonate (14f, IC 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.