Laboratory for Medicinal Chemistry Research, Shionogi & Co., Ltd., 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
Corporate Social Responsibility Department, Shionogi & Co., Ltd., 2F, Nissay Yodoyabashi East, 3-13, Imabashi 3-chome, Chuo-ku, Osaka 541-0042, Japan.
Bioorg Med Chem Lett. 2021 Nov 15;52:128384. doi: 10.1016/j.bmcl.2021.128384. Epub 2021 Sep 26.
In previous work, we discovered a lead compound and conducted initial SAR studies on a novel series of dioxotriazines to identify the compound as one of the P2X3 receptor antagonists. This compound showed high P2X3 receptor selectivity and a strong analgesic effect. Although not selected for clinical development, the compound was evaluated from various aspects as a tool compound. In the course of the following study, the molecular structures of the dioxotriazines were modified based on pharmacokinetic/pharmacodynamic (PK/PD) analyses. As a result of these SAR studies, Sivopixant (S-600918) was identified as a clinical candidate with potent and selective antagonistic activity (P2X3 IC, 4.2 nM; P2X2/3 IC, 1100 nM) and a strong analgesic effect in the rat partial sciatic nerve ligation model (Seltzer model) of allodynia (ED, 0.4 mg/kg).
在之前的工作中，我们发现了一个先导化合物，并对一系列新型的二恶嗪进行了初步的 SAR 研究，以确定该化合物为 P2X3 受体拮抗剂之一。该化合物对 P2X3 受体具有高选择性和强烈的镇痛作用。尽管没有被选为临床开发的药物，但该化合物从各个方面都被评估为一种工具化合物。在随后的研究过程中，根据药代动力学/药效学（PK/PD）分析对二恶嗪的分子结构进行了修饰。通过这些 SAR 研究，确定 Sivopixant（S-600918）为一种具有强大和选择性拮抗活性（P2X3 IC，4.2 nM；P2X2/3 IC，1100 nM）和在大鼠部分坐骨神经结扎模型（Seltzer 模型）中具有强烈镇痛作用的临床候选药物，用于治疗痛觉过敏（ED，0.4 mg/kg）。
