2. Academic Validation
  3. Discovery of clinical candidate Sivopixant (S-600918): Lead optimization of dioxotriazine derivatives as selective P2X3 receptor antagonists

Discovery of clinical candidate Sivopixant (S-600918): Lead optimization of dioxotriazine derivatives as selective P2X3 receptor antagonists

  • Bioorg Med Chem Lett. 2021 Nov 15;52:128384. doi: 10.1016/j.bmcl.2021.128384.
Hiroyuki Kai 1,  Tohru Horiguchi 2,  Takayuki Kameyma 3,  Naohiro Onodera 4,  Naohiro Itoh 5,  Yasuhiko Fujii 6,  Yusuke Ichihashi 4,  Keiichiro Hirai 6,  Takuya Shintani 7,  Kenichiroh Nakamura 3,  Kazuhisa Minami 8,  Erika Kasai 9,  Sosuke Yoneda 9,  Yuki Murakami 4,  Hiroko Ogawa 10,  Ryouko Sekimoto 10,  Shunji Shinohara 4,  Osamu Yoshida 7,  Noriyuki Kurose 4
Affiliations

Affiliations

  • 1 Laboratory for Medicinal Chemistry Research, Shionogi & Co., Ltd., 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan. Electronic address: hiroyuki.kai@shionogi.co.jp.
  • 2 Laboratory for Medicinal Chemistry Research, Shionogi & Co., Ltd., 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan. Electronic address: tooru.horiguchi@shionogi.co.jp.
  • 3 Corporate Social Responsibility Department, Shionogi & Co., Ltd., 2F, Nissay Yodoyabashi East, 3-13, Imabashi 3-chome, Chuo-ku, Osaka 541-0042, Japan.
  • 4 Shionogi TechnoAdvance Research Co., Ltd., 1-1 Futaba-cho, 3-chome, Toyonaka, Osaka 561-0825, Japan.
  • 5 Medical Affairs Department, Shionogi & Co., Ltd., 12F, Hankyu Terminal building, 1-4, Shibata 1-chome, Kita-ku, Osaka 541-0012, Japan.
  • 6 Laboratory for Medicinal Chemistry Research, Shionogi & Co., Ltd., 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
  • 7 Research Management & Planning Office, Shionogi & Co., Ltd., 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
  • 8 Disease Care Strategy Department, Shionogi & Co., Ltd., 1-8 Doshomachi 3-chome, Chuo-ku, Osaka 541-0045, Japan.
  • 9 Laboratory for Drug Discovery & Disease Research, Shionogi & Co., Ltd., 1-1 Futaba-cho, 3-chome, Toyonaka, Osaka 561-0825, Japan.
  • 10 Laboratory for Drug Discovery and Development, Shionogi & Co., Ltd., 1-1 Futaba-cho, 3-chome, Toyonaka, Osaka 561-0825, Japan.
PMID: 34587541 DOI: 10.1016/j.bmcl.2021.128384
Abstract

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 IC50, 4.2 nM; P2X2/3 IC50, 1100 nM) and a strong analgesic effect in the rat partial sciatic nerve ligation model (Seltzer model) of allodynia (ED50, 0.4 mg/kg).

Keywords

Dioxotriazine derivatives; Ion channels; P2X3 receptor antagonists; Pain; Purinergic receptors.

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