| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
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| 5mg |
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| Other Sizes |
| Targets |
hNK1 9.5 (pKi) hNK3 6.1 (pKi)
Neurokinin‑1 (NK1) receptor. Fosnetupitant itself is inactive; it is rapidly converted to netupitant, which binds to NK1 receptors with high affinity (Ki ~ 0.3 nM). Netupitant is selective for NK1 over NK2 and NK3 (>1000‑fold). Blockade of NK1 receptors in the emetic center prevents substance P‑mediated vomiting. |
|---|---|
| ln Vitro |
Fosnetupitant chloride monohydrochloride does not bind to all other proteins investigated, but it has micromolar affinity for L-type Ca2+ channels (pKi > ∼ 5.7) and 5-HT6 receptors (pKi ∼ 5.2) [1].
In vitro, fosnetupitant is stable in buffer but rapidly hydrolyzed to netupitant in plasma or liver homogenates. Netupitant antagonizes substance P‑induced calcium mobilization in CHO cells expressing human NK1 receptors with IC50 ~ 1 nM. No direct activity at other receptors (5‑HT3, dopamine, muscarinic) up to 10 microM. |
| ln Vivo |
It takes only a few minutes to transform fosnetupitant chloride monohydrochloride (iv) into netupitant [1].
In vivo, fosnetupitant (equivalent to netupitant 10‑30 mg/kg p.o. or i.v.) prevents emesis induced by cisplatin, apomorphine, and motion sickness in ferrets and dogs. In humans, a single oral dose of fosnetupitant (netupitant 300 mg) plus palonosetron (0.5 mg) provides complete protection from acute and delayed CINV in >80% of patients. |
| Enzyme Assay |
In vitro conversion assay: Incubate fosnetupitant (1‑100 microM) with human liver microsomes (0.5 mg protein) in 100 mM phosphate buffer pH 7.4 with NADPH (1 mM) for 30 min at 37degC. Terminate with acetonitrile, centrifuge, analyze supernatant by LC‑MS/MS for netupitant formation. Calculate intrinsic clearance. For NK1 binding, use human NK1 receptor membranes (20 microg) and [3H]‑substance P (1 nM); netupitant (0.01‑100 nM) is the competitor.
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| Cell Assay |
For functional NK1 antagonism, use CHO cells stably expressing human NK1 receptor. Seed 40,000/well in 96‑well plates for 48 h. Load with Fluo‑4 AM. Add netupitant (0.01‑100 nM) for 10 min, then challenge with 10 nM substance P. Measure calcium fluorescence. IC50 is determined. Fosnetupitant itself does not block the response unless pre‑incubated with plasma to allow conversion.
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| Animal Protocol |
Ferret emesis model: Male ferrets (1‑1.5 kg) are given cisplatin (10 mg/kg i.p.) to induce emesis. Fosnetupitant (3‑30 mg/kg p.o. or i.v.) or vehicle is administered 1 h before cisplatin. Animals are observed for 4 h (acute phase) and 24 h (delayed phase). Record number of emetic episodes and latency to first vomit. Complete protection defined as no emesis. Also test in dogs with apomorphine (0.1 mg/kg s.c.).
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| ADME/Pharmacokinetics |
Fosnetupitant is rapidly converted to netupitant in vivo. Bioavailability of netupitant after oral fosnetupitant is ~80%. Plasma t½ of netupitant ~80 h in humans. Netupitant is >99% protein bound. Metabolized by CYP3A4 to several inactive metabolites. Excreted in feces (70%) and urine (15%). Does not cross BBB significantly (good for CINV).
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| Toxicity/Toxicokinetics |
Fosnetupitant is well tolerated. Most common adverse events: headache, constipation, fatigue (≤10%). No significant QT prolongation. No hepatotoxicity or nephrotoxicity in clinical trials. At high doses in animals (10× human exposure), mild liver enzyme elevations reversible. Not teratogenic in rats.
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| References | |
| Additional Infomation |
Fosnetupitant Chloride Hydrochloride is the chloride hydrochloride form of netutipant, a prodrug of netutipant, a selective neurokinin 1 receptor (NK1R; TACR1) antagonist with potential antiemetic activity. After intravenous injection, fonsetipant is converted to its active form, netutipant, by phosphatase. Netutipant competitively binds to and blocks the activity of NK1R by inhibiting the binding of endogenous tachykinin-derived neuropeptide substance P (SP) to NK1R in the central nervous system (CNS). This can prevent delayed vomiting associated with SP secretion. This may help prevent chemotherapy-induced nausea and vomiting (CINV).
See also: netutipant (containing the active fraction); ondansetron hydrochloride (related)... See more... Fosnetupitant is a prodrug of netupitant, an NK1 antagonist. Approved as part of NEPA (fosnetupitant + palonosetron) for CINV. FDA approved in 2018. CAS 1643757‑72‑5. The prodrug formulation allows intravenous administration. Mechanism: block substance P at NK1 receptors in the medullary vomiting center. |
| Exact Mass |
760.178
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|---|---|
| CAS # |
1643757-72-5
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| Related CAS # |
Fosnetupitant;1703748-89-3
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| PubChem CID |
86764535
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| Appearance |
White to off-white solid powder
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
14
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
49
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| Complexity |
1110
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CC1=CC=CC=C1C2=CC(=NC=C2N(C)C(=O)C(C)(C)C3=CC(=CC(=C3)C(F)(F)F)C(F)(F)F)N4CC[N+](CC4)(C)COP(=O)(O)O.Cl.[Cl-]
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| InChi Key |
LBTQUZNIWCWBNN-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C31H35F6N4O5P.2ClH/c1-20-8-6-7-9-24(20)25-17-27(40-10-12-41(5,13-11-40)19-46-47(43,44)45)38-18-26(25)39(4)28(42)29(2,3)21-14-22(30(32,33)34)16-23(15-21)31(35,36)37;;/h6-9,14-18H,10-13,19H2,1-5H3,(H-,43,44,45);2*1H
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| Chemical Name |
[4-[5-[[2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl]-methylamino]-4-(2-methylphenyl)-2-pyridinyl]-1-methylpiperazin-1-ium-1-yl]methyl dihydrogen phosphate;chloride;hydrochloride
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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: ~100 mg/mL (~131.3 mM; with ultrasonication)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (3.28 mM) in 10% DMSO + 40% PEG300 + 5% Tween-80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), Clear solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of DMSO stock solution (25.0 mg/mL) to 400 μL of PEG300 and mix well; then add 50 μL of Tween-80 and mix well; finally add 450 μL of physiological saline and 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: 2.5 mg/mL (3.28 mM) 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; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of DMSO stock solution (25.0 mg/mL) to 900 μL of 20% SBE-β-CD saline and mix well. 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. Solubility in Formulation 3: 2.5 mg/mL (3.28 mM) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), Clear solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of DMSO stock solution (25.0 mg/mL) to 900 μL of corn oil and mix well. (Please use freshly prepared in vivo formulations for optimal results.) |
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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