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., 12F, Hankyu Terminal Bldg., 1-4 Shibata 1-chome, Kita-ku, Osaka 530-0012, Japan.
Bioorg Med Chem Lett. 2021 Apr 1;37:127833. doi: 10.1016/j.bmcl.2021.127833. Epub 2021 Feb 2.
P2X receptor is an ATP-gated ion channel, mainly localized on peripheral sensory neurons. Currently, several clinical trials are being conducted with P2X receptor antagonists for the treatment of chronic pain or cough. To identify a P2X lead compound, we reexamined the HTS evaluation compounds and selected dioxotriazine derivatives from which we identified a hit compound. As a result of the hit-to-lead SAR, we obtained lead compound 1 which had a moderate inhibitory effect on P2X receptors (IC, 128 nM). Further improvement of the potency and PK profiles of this lead compound finally led to the selected compound 74 (P2X IC, 16.1 nM; P2X IC, 2931 nM), which demonstrated a strong analgesic effect against allodynia on oral administration in the rat partial sciatic nerve ligation model of neuropathic pain (ED, 3.1 mg/kg).
P2X 受体是一种 ATP 门控离子通道，主要位于周围感觉神经元上。目前，正在进行几项使用 P2X 受体拮抗剂治疗慢性疼痛或咳嗽的临床试验。为了鉴定 P2X 先导化合物，我们重新检查了高通量筛选评估化合物，并从中选择了二恶嗪衍生物，从中我们确定了一个命中化合物。作为命中到先导化合物的 SAR 的结果，我们得到了具有中度抑制 P2X 受体作用的先导化合物 1（IC，128 nM）。进一步改善该先导化合物的效力和 PK 谱，最终导致选择了化合物 74（P2X IC，16.1 nM；P2X IC，2931 nM），其在大鼠部分坐骨神经结扎神经病理性疼痛模型中口服给药时表现出对痛觉过敏的强烈镇痛作用（ED，3.1 mg/kg）。
