Discovery of clinical candidate Sivopixant (S-600918): Lead optimization of dioxotriazine derivatives as selective P2X3 receptor antagonists
Hiroyuki Kai, Tohru Horiguchi, Takayuki Kameyma, Naohiro Onodera, Naohiro Itoh, Yasuhiko Fujii, Yusuke Ichihashi, Keiichiro Hirai, Takuya Shintani, Kenichiroh Nakamura, Kazuhisa Minami, Erika Kasai, Sosuke Yoneda, Yuki Murakami, Hiroko Ogawa, Ryouko Sekimoto, Shunji Shinohara, Osamu Yoshida, Noriyuki Kurose
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).