Novel Series of Dihydropyridinone P2X7 Receptor Antagonists

Identification of singleton P2X7 inhibitor 1 from HTS gave a pharmacophore that eventually turned into potential clinical candidates 17 and 19. During development, a number of issues were successfully addressed, such as metabolic stability, plasma stability, GSH adduct formation, and aniline mutagenicity. Thus, careful modification of the molecule, such as conversion of the 1,4-dihydropyridinone to the 1,2-dihydropyridinone system, proper substitution at C-5″, and in some cases addition of fluorine atoms to the aniline ring allowed for the identification of a novel class of potent P2X7 inhibitors suitable for evaluating the role of P2X7 in inflammatory, immune, neurologic, or musculoskeletal disorders.通过高通量筛选（HTS）得到单靶点P2X7抑制剂1，由此获得的药效团最终开发为潜在临床候选化合物17与19。在开发进程中，研究团队成功解决了多项关键问题，涵盖代谢稳定性、血浆稳定性、谷胱甘肽（GSH）加合物形成以及苯胺致突变性等挑战。为此，通过对分子进行精细化修饰——例如将1,4-二氢吡啶酮结构转化为1,2-二氢吡啶酮体系、在C-5″位引入适宜取代基，且在部分案例中于苯胺环上添加氟原子——最终发现了一类新型强效P2X7抑制剂，可用于评估P2X7在炎症性、免疫性、神经性或肌肉骨骼疾病中的作用。