Szántó Gábor, Makó Attila, Bata Imre, Farkas Bence, Kolok Sándor, Vastag Mónika, Cselenyák Attila
Gedeon Richter Plc, Budapest 10, PO Box 27, H-1475, Hungary.
Bioorg Med Chem Lett. 2016 Aug 15;26(16):3896-904. doi: 10.1016/j.bmcl.2016.07.009. Epub 2016 Jul 5.
Purinergic P2X3 receptors are trimeric ligand-gated ion channels whose antagonism is an appealing yet challenging and not fully validated drug development idea. With the aim of identification of an orally active, potent human P2X3 receptor antagonist compound that can penetrate the central nervous system, the compound collection of Gedeon Richter was screened. A hit series of tricyclic compounds was subjected to a rapid, two-step optimization process focusing on increasing potency, improving metabolic stability and CNS penetrability. Attempts resulted in compound 65, a potential tool compound for testing P2X3 inhibitory effects in vivo.
嘌呤能P2X3受体是三聚体配体门控离子通道，其拮抗作用是一个有吸引力但具有挑战性且尚未完全验证的药物开发理念。为了鉴定一种能够穿透中枢神经系统的口服活性、强效的人P2X3受体拮抗剂化合物，对吉德昂·里奇特公司的化合物库进行了筛选。一系列三环类化合物经过快速的两步优化过程，重点是提高效力、改善代谢稳定性和中枢神经系统渗透性。最终得到了化合物65，它是一种用于在体内测试P2X3抑制作用的潜在工具化合物。
