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

Kai, Hiroyuki; Horiguchi, Tohru; Kameyma, Takayuki; Onodera, Naohiro; Itoh, Naohiro; Fujii, Yasuhiko; Ichihashi, Yusuke; Hirai, Keiichiro; Shintani, Takuya; Nakamura, Kenichiroh; Minami, Kazuhiko; Kasai, Erika; Yoneda, Sosuke; Murakami, Yuki; Ogawa, Hiroko; Sekimoto, Ryouko; Shinohara, Shunji; Yoshida, Osamu; Kurose, Noriyuki

doi:10.1016/j.bmcl.2021.128384

Cited by 17 publications

(13 citation statements)

References 7 publications

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“…The approximately 20-fold selectivity of eliapixant for P2X3 receptors, and its long terminal t ½ leading to a low peak-trough fluctuation, may reduce taste-related AEs by maintaining therapeutic concentrations throughout the dosing period while avoiding excessive peak concentrations that could potentially block P2X2/3 heterotrimers. Two other P2X3 receptor antagonists under development, sivopixant and BLU-5937, have approximately 250-fold and 1000-fold selectivity for P2X3 receptors over P2X2/3 receptors, respectively [32,33]. In a randomized, double-blind, placebo-controlled, phase I study in 90 healthy subjects, BLU-5937 produced taste AEs in 0-6% of subjects receiving doses of 50-100 mg compared with 25-63% at supra-therapeutic doses (400-1200 mg) [34].…”

Section: Discussionmentioning

confidence: 99%

Safety, Pharmacodynamics, and Pharmacokinetics of P2X3 Receptor Antagonist Eliapixant (BAY 1817080) in Healthy Subjects: Double-Blind Randomized Study

et al. 2022

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Background and Objective There is no licensed treatment for refractory chronic cough; off-label therapies have limited efficacy and can produce adverse effects. Excessive adenosine triphosphate signaling via P2X3 receptors is implicated in refractory chronic cough, and selective P2X3 receptor antagonists such as eliapixant (BAY 1817080) are under investigation. The objective of the study was to investigate the safety and tolerability of ascending repeated oral doses of eliapixant in healthy volunteers. Methods We conducted a repeated-dose, double-blind, randomized, placebo-controlled study in 47 healthy male individuals. Subjects received repeated twice-daily ascending oral doses of eliapixant (10, 50, 200, and 750 mg) or placebo for 2 weeks. The primary outcome was frequency and severity of adverse events. Other outcomes included pharmacokinetics and evaluation of taste disturbances, which have occurred with the less selective P2X3 receptor antagonist gefapixant. Results Peak plasma concentrations of eliapixant were reached 3–4 h after administration of the first and subsequent doses. With multiple dosing, steady-state plasma concentrations were reached after ~ 6 days, and plasma concentrations predicted to achieve ≥ 80% P2X3 receptor occupancy (the level required for efficacy) were reached at 200 and 750 mg. Increases in plasma concentrations with increasing doses were less than dose proportional. After multiple dosing, mean plasma concentrations of eliapixant showed low peak–trough fluctuations and were similar for 200- and 750-mg doses. Eliapixant was well tolerated with a low incidence of taste-related adverse events. Conclusions Eliapixant (200 and 750 mg) produced plasma concentrations that cover the predicted therapeutic threshold over 24 h, with good safety and tolerability. These results enabled eliapixant to progress to clinical trials in patients with refractory chronic cough. Clinical Trial Registration Clinicaltrials.gov: NCT03310645 (initial registration: 16 October, 2017). Supplementary Information The online version contains supplementary material available at 10.1007/s40262-022-01126-1.

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Section: Discussionmentioning

confidence: 99%

Safety, Pharmacodynamics, and Pharmacokinetics of P2X3 Receptor Antagonist Eliapixant (BAY 1817080) in Healthy Subjects: Double-Blind Randomized Study

et al. 2022

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“…Sivopixant (also called S-600918), firstly reported by Shionogi, is a newly developed antagonist with favourable pharmacokinetic profiles and higher selectivity to P2X3 over P2X2/3 trimeric homomer [ 95 ]. Its promising antitussive efficacy with limited taste-related side effects for RCC has been demonstrated in a POC phase IIa, randomized, double-blind, placebo-controlled, crossover, multicentre study [ 78 ].…”

Section: P2x Receptor Antagonists In Clinic Trials For Rccmentioning

confidence: 99%

ATP, an attractive target for the treatment of refractory chronic cough

Zhang

Sykes

Sadofsky

et al. 2022

Purinergic Signalling

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Chronic cough is the most common complaint in respiratory clinics. Most of them have identifiable causes and some may respond to common disease-modifying therapies. However, there are many patients whose cough lacks effective aetiologically targeted treatments or remains unexplained after thorough assessments, which have been described as refractory chronic cough. Current treatments for refractory chronic cough are limited and often accompanied by intolerable side effects such as sedation. In recent years, various in-depth researches into the pathogenesis of chronic cough have led to an explosion in the development of drugs for the treatment of refractory chronic cough. There has been considerable progress in the underlying mechanisms of chronic cough targeting ATP, and ongoing or completed clinical studies have confirmed the promising antitussive efficacy of P2X3 antagonists for refractory cough. Herein, we review the foundation on which ATP target was developed as potential antitussive medications and provide an update on current clinical progresses.

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“…Two other non-competitive P2X3 homotrimeric receptor antagonists, BLU-5937 and sivopixant ( Figure 3 ), have a higher selectivity for the P2X3 versus P2X2/3 and are under clinical trial for the treatment of refractory chronic cough [ 56 , 57 ]. Sivopixant showed a strong analgesic effect in the rat partial sciatic nerve ligation model [ 58 ]. A benzimidazole-4,7-dione analog, KCB-77033, was newly identified and showed pain relief in a cisplatin-induced neuropathic pain model [ 59 ].…”

Section: P2x2 and P2x3 Receptorsmentioning

confidence: 99%

The Role of Microglial Purinergic Receptors in Pain Signaling

2022

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Pain is an essential modality of sensation in the body. Purinergic signaling plays an important role in nociceptive pain transmission, under both physiological and pathophysiological conditions, and is important for communication between both neuronal and non-neuronal cells. Microglia and astrocytes express a variety of purinergic effectors, and a variety of receptors play critical roles in the pathogenesis of neuropathic pain. In this review, we discuss our current knowledge of purinergic signaling and of the compounds that modulate purinergic transmission, with the aim of highlighting the importance of purinergic pathways as targets for the treatment of persistent pain.

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

Cited by 17 publications

References 7 publications

Safety, Pharmacodynamics, and Pharmacokinetics of P2X3 Receptor Antagonist Eliapixant (BAY 1817080) in Healthy Subjects: Double-Blind Randomized Study

Safety, Pharmacodynamics, and Pharmacokinetics of P2X3 Receptor Antagonist Eliapixant (BAY 1817080) in Healthy Subjects: Double-Blind Randomized Study

ATP, an attractive target for the treatment of refractory chronic cough

The Role of Microglial Purinergic Receptors in Pain Signaling

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