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| Targets |
The primary target of rolapitant is the neurokinin-1 receptor (NK1 receptor), a member of the G protein-coupled receptor family. It competitively binds to and blocks the activity of the NK1 receptor in the central nervous system, thereby inhibiting the interaction with the endogenous ligand substance P. Rolapitant exhibits high affinity for the human NK1 receptor with a Ki value of 0.66 nM and demonstrates >1000-fold selectivity over the human NK2 and NK3 subtypes. Compared to other NK1 receptor antagonists like aprepitant, rolapitant has both a more rapid onset of action and a much longer half-life.
Rolapitant HCl targets the neurokinin 1 (NK1) receptor, a G protein-coupled receptor for the neuropeptide substance P. Substance P is a key mediator of emesis, and NK1 receptor antagonists are effective in preventing chemotherapy-induced nausea and vomiting (CINV). Rolapitant HCl is a potent antagonist with a Ki of 0.66 nM. Its long-acting property allows for once-daily or less frequent dosing. The compound does not interact with CYP3A4, reducing the risk of drug-drug interactions. |
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| ln Vitro |
Rolapitant exhibits superior affinity for NK1 receptors in humans, guinea pigs, gerbils, and monkeys compared to rat, mouse, and rabbit, and it has over 1000-fold selectivity for human NK2 and NK3 isoforms [1]. In CHO cells expressing human NK1 receptor, rolapitant (1-1000 nM) competitively and concentration-dependently blocks calcium efflux generated by GR-73632, an NK1 receptor agonist [1].
Rolapitant demonstrates high selectivity and potent NK1 receptor antagonistic activity in vitro. In cell-free radioligand binding assays, rolapitant exhibits high affinity for the human NK1 receptor with a Ki value of 0.66 nM and displays >1000-fold selectivity over the human NK2 and NK3 subtypes. In CHO cells expressing the human NK1 receptor, rolapitant (1-1000 nM) inhibits GR-73632 (an NK1 receptor agonist)-induced calcium efflux in a concentration-dependent and competitive manner, with a calculated Kb value of 0.17 nM. Furthermore, rolapitant exhibits species selectivity for the NK1 receptor, showing preferential affinity for human, guinea pig, gerbil, and monkey NK1 receptors over rat, mouse, and rabbit. In vitro, Rolapitant HCl is a potent NK1 receptor antagonist with a Ki of 0.66 nM. It shows high selectivity for the NK1 receptor. The compound does not interact with CYP3A4, which is a significant advantage over other NK1 antagonists that may have drug-drug interactions. Its long-acting property is also evident in vitro, with slow dissociation from the receptor. |
| ln Vivo |
In Mongolian gerbils, rolapitant (0.03–1 mg/kg orally, 0.3–1 mg/kg intravenously; single dose) reduces the foot tapping response induced by GR-73632 [1]. Rolapitant (0.03-1 mg/kg; oral; single dose; observed for 72 hours) inhibits the acute vomiting that ferrets experience when given apomorphine and cisplatin [1].
Rolapitant demonstrates centrally-mediated antiemetic activity in various animal models. In gerbils, a single oral or intravenous administration of rolapitant (minimal effective dose of 0.1 mg/kg) reverses NK1 agonist-induced foot-tapping response for up to 24 hours. In ferrets, rolapitant (0.03-1 mg/kg, oral) effectively blocks apomorphine- and cisplatin-induced acute emesis and shows activity in both acute and delayed emesis models at 0.1 and 1 mg/kg, respectively. Clinical efficacy of antiemetics is highly correlated with efficacy in the ferret emesis model, suggesting rolapitant's clinical effectiveness. In vivo, Rolapitant HCl demonstrates potent centrally-mediated anti-emetic activity. In ferret emesis models, it is effective in both acute and delayed phases of emesis. The compound is orally active and has a long duration of action. It is used clinically for the prevention of chemotherapy-induced nausea and vomiting (CINV). Its lack of CYP3A4 interaction reduces the risk of drug-drug interactions with chemotherapeutic agents. |
| Enzyme Assay |
Membrane Preparation: Harvest CHO cells expressing human NK1 receptors, lyse cells, and extract membrane fractions via centrifugation.
Radioligand Binding Assay: Incubate membranes with radioligand (e.g., [³H]substance P or [³H]GR-73632) and various concentrations of rolapitant in assay buffer at room temperature.
Define Non-specific Binding: Use a high concentration of unlabeled ligand or NK1 receptor antagonist to define non-specific binding.
Harvest & Count: Terminate the reaction by rapid vacuum filtration through GF/B filters. Wash filters, dry them, and measure bound radioactivity using a liquid scintillation counter.
Data Analysis: Plot competitive binding curves and calculate the Ki value for rolapitant (0.66 nM).
In vitro receptor binding assays are used to characterize Rolapitant HCl's interaction with the NK1 receptor. Membrane preparations from cells expressing the human NK1 receptor are incubated with a radiolabeled antagonist and varying concentrations of Rolapitant HCl. The displacement of the radioligand is measured, and the Ki value (0.66 nM) is calculated. Selectivity is assessed by testing against other neurokinin receptors and a panel of off-target receptors. CYP3A4 interaction is assessed using standard in vitro CYP inhibition assays. |
| Cell Assay |
Cell Culture: Seed CHO cells stably expressing human NK1 receptors into appropriate culture plates and culture to suitable confluence.
Calcium Flux Assay: Load cells with a calcium-sensitive dye (e.g., Fluo-4 AM) and pre-incubate with varying concentrations of rolapitant.
Agonist Stimulation: Add NK1 receptor agonist GR-73632 to stimulate, and detect changes in intracellular calcium concentration using a fluorescence plate reader or HTS system.
Data Analysis: Rolapitant inhibits agonist-induced calcium efflux in a concentration-dependent and competitive manner, with a calculated Kb value of 0.17 nM.
In vitro cell-based assays for Rolapitant HCl are conducted in cells expressing the NK1 receptor. Cells are treated with the compound, and its ability to inhibit substance P-induced calcium mobilization or other signaling pathways is measured. These functional assays confirm the compound's antagonistic properties. The compound's lack of CYP3A4 interaction is confirmed using hepatocyte or microsome-based assays. |
| Animal Protocol |
Animal/Disease Models: Female Mongolian gerbil (30-60 g; anesthetized with oxygen:isoflurane mixture immediately after 4 h PO or immediately after IV, followed by ICV injection of 5 μl of 3 pmol GR-73632 solution) [1]
Doses: 0.03 orally , 0.1, 0.3 and 1 mg/kg, IV 0.3 and 1 mg/kg Dosing: Oral or IV, single dose Experimental Results: GR-73632-induced foot tapping response was attenuated when administered PO 4, dose-dependent One hour before the dependence test, the ID90 is 0.3 mg/kg, and foot pedaling is inhibited for at least 24 hrs (hrs (hours)). When administered intravenously (iv) (iv)(iv), GR-73632 induced a dose-dependent blockade of foot tapping, with complete blockade observed at 1 mg/kg. Animal/Disease Models: Ferrets (treated with 0.125 mg/kg apomorphine subcutaneously (sc) (sc) or 10 mg/kg cisplatin intraperitoneally (ip) (ip)) [1] Doses: 0.03, 0.1, 0.3 and 1 mg/kg Route of Administration: PO; single dose; Results observed for 72 hrs (hrs (hours)): Blocked dose-dependent acute vomiting in ferrets induced by apomorphine and cisplatin. Retching and vomiting were significan In vivo animal experiments with Rolapitant HCl are conducted in ferret emesis models. Ferrets are treated with the compound orally or intravenously, and emesis is induced by a chemotherapeutic agent (e.g., cisplatin). The number of emetic episodes and the latency to emesis are recorded. The compound's efficacy in both acute and delayed phases is assessed. These studies demonstrate its potent anti-emetic activity and long duration of action. |
| ADME/Pharmacokinetics |
Pharmacokinetic properties of Rolapitant HCl include good oral bioavailability and a long half-life, supporting once-daily dosing. The compound has a molecular formula of C25H27ClF6N2O2 and a molecular weight of 536.94. It does not interact with CYP3A4, reducing the risk of drug-drug interactions. The compound is metabolized primarily by other CYP enzymes and excreted in the urine and feces. Specific PK parameters (Cmax, Tmax, AUC) are available from clinical studies.
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| Toxicity/Toxicokinetics |
Rolapitant HCl has been evaluated in clinical trials and is approved for the prevention of chemotherapy-induced nausea and vomiting (CINV). Common adverse effects include fatigue, neutropenia, hiccups, and decreased appetite. As an NK1 receptor antagonist, it may also cause central nervous system effects such as dizziness. The compound is contraindicated in patients with hypersensitivity. It is pregnancy category C. Standard safety precautions apply.
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| References |
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| Additional Infomation |
Rolapitant hydrochloride (anhydrous form) is the hydrochloride salt of irinotecan reacted with an equimolar amount of hydrochloric acid. It (in hydrated form) is used to prevent delayed nausea and vomiting induced by initial and repeated courses of emetogenic chemotherapy for cancer. It has antiemetic and neurokinin-1 receptor antagonistic effects. It contains rorapitan (1+).
See also: Rolapitant hydrochloride (note moved to). Rolapitant HCl has CAS number 858102-79-1, molecular formula C25H27ClF6N2O2, and molecular weight 536.94. It is a potent, selective, long-acting, and orally active NK1 receptor antagonist with a Ki of 0.66 nM. It does not interact with CYP3A4. It is used for the prevention of chemotherapy-induced nausea and vomiting. Purity: typically ≥98%. Not for over-the-counter use; for prescription and research applications. |
| Molecular Formula |
C25H27CLF6N2O2
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|---|---|
| Molecular Weight |
536.937506914139
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| Exact Mass |
536.167
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| Elemental Analysis |
C, 55.92; H, 5.07; Cl, 6.60; F, 21.23; N, 5.22; O, 5.96
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| CAS # |
858102-79-1
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| Related CAS # |
Rolapitant;552292-08-7;Rolapitant hydrochloride hydrate;914462-92-3
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| PubChem CID |
71587824
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| Appearance |
Typically exists as solid at room temperature
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| LogP |
7.189
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
36
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| Complexity |
731
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| Defined Atom Stereocenter Count |
3
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| SMILES |
Cl.FC(C1C=C(C(F)(F)F)C=C(C=1)[C@@H](C)OC[C@@]1(C2C=CC=CC=2)CC[C@]2(CCC(N2)=O)CN1)(F)F
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| InChi Key |
VEWAWEMXVUFANV-PVBCUUEWSA-N
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| InChi Code |
InChI=1S/C25H26F6N2O2.ClH/c1-16(17-11-19(24(26,27)28)13-20(12-17)25(29,30)31)35-15-23(18-5-3-2-4-6-18)10-9-22(14-32-23)8-7-21(34)33-22;/h2-6,11-13,16,32H,7-10,14-15H2,1H3,(H,33,34);1H/t16-,22-,23-;/m1./s1
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| Chemical Name |
(5S,8S)-8-[[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]methyl]-8-phenyl-1,9-diazaspiro[4.5]decan-2-one;hydrochloride
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| Synonyms |
858102-79-1; Rolapitant (hydrochloride); (5S,8S)-8-[[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]methyl]-8-phenyl-1,9-diazaspiro[4.5]decan-2-one;hydrochloride; C25H27ClF6N2O2; 1,7-Diazaspiro[4.5]decan-2-one, 8-[[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]methyl]-8-phenyl-, hydrochloride (1:1), (5S,8S)-; 1,7-Diazaspiro[4.5]decan-2-one, 8-[[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]methyl]-8-phenyl-, monohydrochloride, (5S,8S)- (9CI); Rolapitant hydrochloride; Sch 619734;
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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 | 1.8624 mL | 9.3120 mL | 18.6241 mL | |
| 5 mM | 0.3725 mL | 1.8624 mL | 3.7248 mL | |
| 10 mM | 0.1862 mL | 0.9312 mL | 1.8624 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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