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
  • 1. Laboratory for Medicinal Chemistry Research, Shionogi & Co., Ltd., 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan. Electronic address: [email protected].
  • 2. Laboratory for Medicinal Chemistry Research, Shionogi & Co., Ltd., 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan. Electronic address: [email protected].
  • 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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