School of Chemistry, University of Sydney, NSW, Australia.
School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich, UK.
Expert Opin Ther Pat. 2022 Jul;32(7):769-790. doi: 10.1080/13543776.2022.2069010. Epub 2022 May 11.
Purinergic receptors play a critical role in neurotransmission, and modulation of complex physiological functions and thus have implications in numerous disease states. The past decade has seen substantial progress in the design of novel chemical compounds that act on the P2X class of receptors and warrants an updated review of this field.
This review provides a summary of the patent literature describing the discovery and clinical uses of P2X receptor antagonists published between 2010 and September 2021. The reader will gain information on structural claims, representative structures, and biological data of recently reported P2X antagonists.
Despite continual advancement in both crystallography and chemical biology strengthening our understanding of purinergic signalling, there remains an absence of clinically approved chemotypes. A testament to both the therapeutic potential and academic perseverance in purinergic research is the multitude of research initiatives that maintain active P2X receptor programs that have spanned decades. Very recently, the FDA declined Merck Pharmaceuticals application for Gefapixant, a P2X3 selective inhibitor as a treatment for chronic cough, requesting additional data. This unfortunate setback will ultimately be insignificant considering the long history of P2X investigation and the preclinical and clinical development that will undoubtedly occur over the next decade.
嘌呤能受体在神经传递中起着关键作用，并调节复杂的生理功能，因此与许多疾病状态有关。在过去的十年中，设计作用于 P2X 类受体的新型化学化合物方面取得了重大进展，因此有必要对此领域进行更新的综述。
本综述总结了描述 2010 年至 2021 年 9 月期间发表的 P2X 受体拮抗剂的专利文献。读者将了解到结构权利要求、代表性结构和最近报道的 P2X 拮抗剂的生物学数据。
尽管晶体学和化学生物学的不断进步加强了我们对嘌呤能信号转导的理解，但仍然缺乏临床批准的化学型。这证明了 P2X 受体研究的治疗潜力和学术毅力，有许多研究计划一直在进行，这些计划跨越了几十年。最近，美国食品和药物管理局（FDA）拒绝了默克制药公司 Gefapixant 的申请，该药物是一种 P2X3 选择性抑制剂，用于治疗慢性咳嗽，并要求提供更多数据。考虑到 P2X 研究的悠久历史以及未来十年无疑将进行的临床前和临床开发，这种不幸的挫折最终将是微不足道的。
