吡咯烷酮衍生物作为 P2X3 受体拮抗剂的一个新类别。第 2 部分：口服生物利用化合物的发现。
Pyrrolinone derivatives as a new class of P2X3 receptor antagonists Part 2: Discovery of orally bioavailable compounds.
机构信息
Medicinal Chemistry Research Laboratory, Shionogi & Co., Ltd., 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
Office for Children's Bright Future, Shionogi & Co., Ltd., 2F, Nissay Yodoyabashi East, 3-13, Imabashi 3-chome, Chuo-ku, Osaka 541-0042, Japan.
出版信息
Bioorg Med Chem Lett. 2019 Mar 1;29(5):688-693. doi: 10.1016/j.bmcl.2019.01.039. Epub 2019 Feb 1.
Some P2X3 receptor antagonists have been developed as new therapeutic drugs for pain. We discovered a novel chemotype of P2X3 receptor antagonists with a pyrrolinone skeleton. Because of SAR studies to improve bioavailability of lead compound 2, compound (R)-24 was identified, which showed an analgesic effect against neuropathic pain by oral administration. We constructed a human P2X3 homology model as a template for the zebrafish P2X4 receptor, which agreed with SAR studies of pyrrolinone derivatives.
一些 P2X3 受体拮抗剂已被开发为治疗疼痛的新型治疗药物。我们发现了一种具有吡咯啉酮骨架的新型 P2X3 受体拮抗剂化学型。由于为提高先导化合物 2 的生物利用度而进行的 SAR 研究，确定了化合物 (R)-24，其通过口服给药显示出抗神经病理性疼痛的作用。我们构建了一个人 P2X3 同源模型作为斑马鱼 P2X4 受体的模板，这与吡咯啉酮衍生物的 SAR 研究一致。
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