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| Targets |
Sivopixant is a potent and selective antagonist of the P2X3 homotrimeric receptor. It exhibits an IC50 of 4.2 nM for P2X3 homotrimers and 1100 nM for P2X2/3 heterotrimers, representing approximately 250-fold selectivity for the homotrimeric receptor. This high selectivity is believed to minimize off-target effects such as taste disturbance. The P2X3 receptor is involved in pain signaling and the cough reflex.
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| ln Vitro |
In vitro, sivopixant is a potent and selective P2X3 homotrimeric antagonist with an IC50 of 4.2 nM and 250-fold selectivity over P2X2/3 heterotrimers (IC50 = 1100 nM). It has been identified as a clinical candidate with potent and selective antagonistic activity. The compound shows excellent absorbability and a balanced PK profile in preclinical species. In rat DRG neuron assays, sivopixant potently blocks P2X3-mediated currents and sensitization.
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| ln Vivo |
In the rat Seltzer model of allodynia (ED50=0.4 mg/kg), sivopixant (S-600918) (iv; 1 mg/kg) exhibits a substantial analgesic effect and a longer half-life (T1/2= 10.1 hours)[1].
In vivo, sivopixant shows a strong analgesic effect in the rat partial sciatic nerve ligation model (Seltzer model) of allodynia, with an ED50 of 0.4 mg/kg. It has also been advanced as an oral phase II candidate for the study of refractory chronic cough. The compound's potent antagonism combined with its favorable PK profile supports once- or twice-daily oral dosing in clinical studies. |
| Enzyme Assay |
Sivopixant's in vitro P2X3 antagonism is typically assessed in HEK293 cells stably expressing human P2X3 receptors loaded with a calcium-sensitive dye (e.g., Fluo-4). Cells are pre-incubated with sivopixant (0.01-1000 nM) for 5-10 minutes, then stimulated with ATP (1-100 uM). The resulting calcium flux is measured using a fluorescence plate reader. IC50 values are calculated from dose-response curves. For selectivity, similar assays are performed on cells expressing P2X2/3 heterodimers.
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| Cell Assay |
For cell-based assays, primary cultures of rat dorsal root ganglion (DRG) neurons are treated with sivopixant at concentrations ranging from 1-1000 nM for 30-60 minutes. Neurons are then stimulated with ATP (10 uM) to activate P2X3 homotrimeric receptors. P2X3-mediated calcium influx is measured by ratiometric imaging using Fura-2 AM. Whole-cell patch-clamp recordings can also be used to measure ATP-evoked currents. Neuronal sensitization is assessed by measuring action potential firing frequency. Cell viability is evaluated by LDH assay.
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| Animal Protocol |
For in vivo efficacy studies, sivopixant is formulated in a suitable oral vehicle (e.g., 0.5% methylcellulose or PEG400) and administered orally by gavage to rats at doses ranging from 0.1-10 mg/kg. In the partial sciatic nerve ligation (Seltzer) model, nerve injury is induced 7-14 days prior to drug administration. Tactile allodynia is measured using von Frey filaments before and at various time points (0.5-6 hours) post-dose. The ED50 for analgesic effect is approximately 0.4 mg/kg. For cough models, guinea pigs are used.
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| ADME/Pharmacokinetics |
Pharmacokinetic studies in preclinical species (e.g., rats and dogs) show that sivopixant exhibits excellent absorbability and a balanced PK profile. The compound has good oral bioavailability and a half-life suitable for once-daily dosing. Specific PK parameters (Cmax, Tmax, t1/2, AUC, oral bioavailability) are available in primary literature, particularly in the medicinal chemistry publication by Kai et al. (Bioorg Med Chem Lett. 2021). Researchers should consult this reference for detailed PK data.
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| Toxicity/Toxicokinetics |
Toxicology data for sivopixant have been generated as part of preclinical development to support clinical trials. In animal studies at doses up to 30 mg/kg, no significant adverse effects have been reported. The compound's high selectivity for P2X3 homotrimers over P2X2/3 heterotrimers is thought to minimize taste disturbance, a common side effect of other P2X3 antagonists. Comprehensive toxicology reports are not publicly available.
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| References | |
| Additional Infomation |
Drug Indication
Treatment of unexplained or refractory chronic cough. Sivopixant is an oral Phase II clinical candidate for the treatment of refractory chronic cough. It was originally developed as an analgesic for pain relief and showed a strong analgesic effect in neuropathic pain models before being repurposed for chronic cough. The compound is the result of lead optimization of dioxotriazine derivatives as selective P2X3 receptor antagonists. Sivopixant is not approved for clinical use and is for research purposes only. |
| Molecular Formula |
C25H22CLN5O5
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|---|---|
| Molecular Weight |
507.93
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| Exact Mass |
507.13
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| CAS # |
2414285-40-6
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| Related CAS # |
(E/Z)-Sivopixant;1640808-39-4
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| PubChem CID |
117752163
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| Appearance |
White to off-white solid powder
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| LogP |
3.8
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
36
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| Complexity |
826
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C(C1C=CC(Cl)=CC=1)N1C(N(C[C@H](C)C(=O)O)C(=O)N=C1NC1C=CC(OC2N=CC=CC=2)=CC=1)=O
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| InChi Key |
SKZQFKBIJUXXCG-INIZCTEOSA-N
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| InChi Code |
InChI=1S/C25H22ClN5O5/c1-16(22(32)33)14-31-24(34)29-23(30(25(31)35)15-17-5-7-18(26)8-6-17)28-19-9-11-20(12-10-19)36-21-4-2-3-13-27-21/h2-13,16H,14-15H2,1H3,(H,32,33)(H,28,29,34)/t16-/m0/s1
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| Chemical Name |
(2S)-3-[3-[(4-chlorophenyl)methyl]-2,6-dioxo-4-(4-pyridin-2-yloxyanilino)-1,3,5-triazin-1-yl]-2-methylpropanoic acid
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9688 mL | 9.8439 mL | 19.6878 mL | |
| 5 mM | 0.3938 mL | 1.9688 mL | 3.9376 mL | |
| 10 mM | 0.1969 mL | 0.9844 mL | 1.9688 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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