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| Targets |
Casopitant's target is the neurokinin 1 (NK1) receptor, a G-protein coupled receptor found in both the nucleus tractus solitarii and the area postrema of the brainstem. These areas are part of the chemoreceptor trigger zone (CTZ) and are involved in the vomiting reflex. By competitively binding to and blocking the NK1 receptor, Casopitant inhibits the binding of substance P. Substance P is a neuropeptide that, when released in response to emetogenic stimuli, activates the NK1 receptor to initiate the vomiting reflex.
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| ln Vitro |
Casopitant is a potent and selective NK1 receptor antagonist. In vitro studies typically involve binding assays to determine its affinity for the NK1 receptor. The compound is also a substrate and weak-to-moderate inhibitor of the cytochrome P450 enzyme CYP3A4. This is an important consideration for its potential drug-drug interactions, as many other drugs are metabolized by this enzyme. Its antiemetic activity is confirmed in functional assays where it inhibits substance P-induced signaling.
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| ln Vivo |
Casopitant (GW679769) decreased nausea-like behavior and suppressed retching and vomiting in a ferret model of cisplatin-induced emesis in a dose-dependent manner. In a ferret model of cisplatin-induced emesis, the pharmacokinetics and brain permeability of casopitant were investigated. Radiation-labeled casopitant ([14C]Casopitant) is quickly absorbed after a single intraperitoneal injection; two hours after delivery, the concentrations in the brain and plasma are roughly identical. [14C]Casopitant is found in the brain as the parent compound and as two major oxidative metabolites (M1 and M2). These metabolites account for roughly 76%, 19%, and 3% of the radioactivity, respectively; this suggests that the parent compound is responsible for a significant portion of the radioactivity in ferrets. In the brain of a ferret, captopritant binds with great affinity to the NK1 receptor [2].
The in vivo antiemetic activity of Casopitant has been demonstrated in animal models, such as the ferret model of cisplatin-induced emesis. In these studies, Casopitant dose-dependently decreased nausea-like behavior and suppressed retching and vomiting. These results confirmed its mechanism of action and supported its clinical development as an antiemetic agent. The compound is orally active, making it convenient for administration in a clinical setting. |
| Enzyme Assay |
The affinity of Casopitant for the NK1 receptor is typically determined using radioligand binding assays. In these cell-free experiments, the NK1 receptor (often from human or animal sources) is incubated with a radiolabeled ligand (e.g., [3H]-substance P) and varying concentrations of Casopitant. After incubation, the bound and free radioligand are separated, and the amount of bound radioligand is measured. The concentration of Casopitant that displaces 50% of the specific binding (IC50) is calculated, providing a measure of its receptor binding affinity.
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| Cell Assay |
Cellular assays for Casopitant involve studying its effect on substance P-induced signaling. A common protocol uses cells that naturally express the NK1 receptor or are engineered to do so. These cells are loaded with a calcium-sensitive fluorescent dye. Substance P stimulation leads to a rapid increase in intracellular calcium, which is detected as a fluorescence signal. Casopitant is pre-incubated with the cells, and its ability to inhibit the substance P-induced calcium flux is measured. This functional assay confirms receptor antagonism.
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| Animal Protocol |
The in vivo efficacy of Casopitant is primarily evaluated in the ferret cisplatin-induced emesis model, a standard model for testing antiemetic agents. In this protocol, ferrets are administered cisplatin to induce emesis. Casopitant is administered at various doses and routes (e.g., oral or intravenous) before the cisplatin challenge. The animals are then observed for a set period (e.g., 4-6 hours), and the number of retching and vomiting episodes is recorded. The effective dose that reduces emesis by a certain percentage (e.g., ED50) is calculated.
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| ADME/Pharmacokinetics |
Casopitant is an orally bioavailable compound with a molecular weight suitable for small molecule drug development. It is metabolized primarily by the cytochrome P450 enzyme CYP3A4, which is a key consideration for its pharmacokinetic profile and potential drug interactions. The mesylate salt form (Casopitant mesylate) enhances its solubility and oral bioavailability, making it suitable for oral administration in clinical settings.
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| Toxicity/Toxicokinetics |
The safety and toxicity of Casopitant were extensively evaluated in preclinical and clinical studies. As a NK1 receptor antagonist, its primary effects are related to its pharmacological action. However, like all drugs, it has a potential for side effects and toxicity at high doses. In vitro data indicate its potential to interact with CYP3A4, which could lead to altered metabolism of co-administered drugs. Standard toxicology studies were conducted to determine its safety profile and establish safe dosing ranges for clinical trials.
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| References |
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| Additional Infomation |
Casopitant mesylate is a mesylate salt of a central nervous system kinin 1 (NK1) receptor antagonist with antidepressant and antiemetic activities. Casopitant competitively binds to and blocks the activity of the NK1 receptor, thereby inhibiting the binding of the endogenous tachykinin neuropeptide P (SP) to the NK1 receptor, which may produce an antiemetic effect. SP is present in neurons innervating vagal afferent fibers of the nucleus tractus solitarius and the post-traumatic zone (containing the chemoreceptor trigger zone (CTZ)) in the brainstem; SP levels may increase after chemotherapy. The NK1 receptor is a G protein-coupled receptor coupled to the inositol phosphate signaling pathway and is present in the nucleus tractus solitarius and the post-traumatic zone.
Casopitant mesylate is a second-generation antiemetic that acts as a neurokinin-1 (NK1) receptor antagonist. It was developed for the prevention of chemotherapy-induced and postoperative nausea and vomiting. While it showed promise in clinical trials, its development and regulatory approval status have been subject to various factors. It is an example of a centrally-acting agent that targets the substance P/NK1 receptor pathway in the brainstem to control emesis. The compound is also known as GW679769. |
| Molecular Formula |
C31H39F7N4O5S
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|---|---|
| Molecular Weight |
712.718991518021
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| Exact Mass |
712.253
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| Elemental Analysis |
C, 52.24; H, 5.52; F, 18.66; N, 7.86; O, 11.22; S, 4.50
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| CAS # |
414910-30-8
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| Related CAS # |
414910-30-8 (mesylate);414910-27-3;
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| PubChem CID |
11686295
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| Appearance |
White to off-white solid powder
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| LogP |
7.052
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
13
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
48
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| Complexity |
1040
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| Defined Atom Stereocenter Count |
3
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| SMILES |
CC1=C(C=CC(=C1)F)[C@H]2C[C@H](CCN2C(=O)N(C)[C@H](C)C3=CC(=CC(=C3)C(F)(F)F)C(F)(F)F)N4CCN(CC4)C(=O)C.CS(=O)(=O)O
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| InChi Key |
YRFKYVWDPCOSTE-REWBLLDVSA-N
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| InChi Code |
InChI=1S/C30H35F7N4O2.CH4O3S/c1-18-13-24(31)5-6-26(18)27-17-25(40-11-9-39(10-12-40)20(3)42)7-8-41(27)28(43)38(4)19(2)21-14-22(29(32,33)34)16-23(15-21)30(35,36)37;1-5(2,3)4/h5-6,13-16,19,25,27H,7-12,17H2,1-4H3;1H3,(H,2,3,4)/t19-,25+,27-;/m1./s1
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| Chemical Name |
(2R,4S)-4-(4-acetylpiperazin-1-yl)-N-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]-2-(4-fluoro-2-methylphenyl)-N-methylpiperidine-1-carboxamide;methanesulfonic acid
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| Synonyms |
Casopitant mesylate; GW679769 mesylate; 414910-30-8; casopitant mesilate; GW679769B; GW-679769B;
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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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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) |
DMSO : ~33.33 mg/mL (~46.76 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 0.71 mg/mL (1.00 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 7.1 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 0.71 mg/mL (1.00 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 7.1 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 0.71 mg/mL (1.00 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.4031 mL | 7.0154 mL | 14.0308 mL | |
| 5 mM | 0.2806 mL | 1.4031 mL | 2.8062 mL | |
| 10 mM | 0.1403 mL | 0.7015 mL | 1.4031 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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