Discovery of 5-methyl-1H-benzo[d]imidazole derivatives as novel P2X3 Receptor antagonists

Drug discovery programs targeting P2X3 receptors (P2X3R), an extracellular adenosine 5 & PRIME;-triphosphate (ATP) gated cation channel family, have been actively investigated for several CNS-related diseases. The current unmet need in the field of P2X3R targeted drugs is to avoid a side effect, the loss of taste, that could be reduced by increase of the P2X3R selectivity vs P2X2/3R. In this study, 5-methyl-1H-benzo[d]imidazole derivatives were designed and synthesized from the analysis of key pharmacophores of current antagonists. In the structure-activity relationship study, the most potent compounds 17a -b was discovered as potent P2X3R antagonists with IC50 values of 145 and 206 nM, and selectivity index of 60 and 41, respectively. In addition, 17a -b showed the not-competitive antagonism, but poor binding score in the docking study at the known allosteric binding site of Gefapixant binding site, indicating that another allosteric binding site might be existing for the novel P2X3R antagonists.

Automated summary

This study designed and synthesized 5-methyl-1H-benzo[d]imidazole derivatives and discovered that compounds 17a and 17b exhibited strong P2X3R antagonistic activity and selectivity. The study also suggested the existence of another allosteric binding site for the novel P2X3R antagonists.