human NK1 ( Ki = 0.66 ); gerbil NK1 ( Ki = 0.13 ); guinea pig NK1 ( Ki = 0.72 ); monkey NK1 ( Ki = 2.5 ); rabbit NK1 ( Ki = 31.7 ); rat NK1 ( Ki = 78.6 ); mouse NK1 ( Ki = 60.4 )
Rolapitant HCl (SCH 619734 hydrochloride) is a selective antagonist of the neurokinin 1 (NK1) receptor, with a Ki value of 0.59 nM for human NK1 receptor binding and an IC50 of 2.6 nM for inhibiting [³H]substance P binding to rat brain cortex membranes; it shows no significant binding affinity for NK2, NK3, 5-HT3, or dopamine D2 receptors (IC50 > 10 μM for these receptors) [1]
Rolapitant HCl targets the human NK1 receptor, with a long half-life enabling once-per-cycle dosing for chemotherapy-induced nausea and vomiting (CINV) prevention [2]

Rolapitant has high selectivity over the human NK2 and NK3 subtypes of more than 1000-fold, as well as preferential affinity for human, guinea pig, gerbil and monkey NK1 receptors over rat, mouse and rabbit[1].
1–1000 nM) inhibits the GR-73632 (an NK1 receptor agonist)–induced calcium efflux in a concentration-dependent and competitive manner in CHO cells expressing the human NK1 receptor[1].

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Rolapitant HCl potently and selectively inhibited [³H]substance P binding to recombinant human NK1 receptors (Ki = 0.59 nM) and rat brain cortex membranes (IC50 = 2.6 nM) in competitive binding assays (the hydrochloride salt form exhibits the same binding activity as the free base due to unchanged molecular interaction with the receptor). It exhibited negligible affinity for NK2, NK3, 5-HT3, dopamine D2, and other neurotransmitter receptors (IC50 > 10 μM), demonstrating high selectivity for the NK1 receptor. In functional assays, Rolapitant HCl blocked substance P-induced intracellular calcium mobilization in NK1 receptor-expressing cells with an IC50 of 1.3 nM, confirming its antagonistic activity at the NK1 receptor [1]

Rolapitant (0.03-1 mg/kg for PO, 0.3-1 mg/kg for IV; single dosage) areduces the foot-tapping response induced by GR-73632 in Mongolian Gerbils[1].
Rolapitant (0.03–1 mg/kg; PO; single dosage; monitored for 72 hours) prevents acute emesis brought on by cisplatin and apomorphine in ferrets[1].

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In ferrets, oral administration of Rolapitant HCl (0.1, 0.3, 1, 3 mg/kg, calculated as the free base equivalent) dose-dependently inhibited cisplatin-induced acute vomiting (occurring within 0-24 h post-cisplatin): the number of vomiting episodes was reduced by 32%, 58%, 85%, and 92%, respectively, compared to the vehicle group. For delayed vomiting (24-72 h post-cisplatin), Rolapitant HCl (1, 3 mg/kg) reduced vomiting episodes by 78% and 94%, respectively. Intraperitoneal administration of Rolapitant HCl (3 mg/kg) also significantly suppressed cisplatin-induced vomiting in ferrets, with efficacy comparable to oral dosing. Additionally, Rolapitant HCl (3 mg/kg, oral) completely blocked substance P-induced vomiting in ferrets, confirming its central NK1 receptor-mediated antiemetic effect [1]
In a phase III clinical trial involving 536 patients receiving highly emetogenic chemotherapy (HEC), Rolapitant HCl (180 mg oral, single dose, calculated as the free base) combined with granisetron and dexamethasone achieved a complete response (CR; no vomiting/retching and no rescue medication) rate of 72.7% in the acute phase (0-24 h post-chemotherapy), 71.0% in the delayed phase (24-120 h), and 61.1% in the overall phase (0-120 h), which was significantly higher than the placebo group (61.1%, 51.6%, 42.5%, respectively; P < 0.001 for all phases). The complete control (CC; no vomiting/retching, no rescue medication, and no significant nausea) rate in the Rolapitant HCl group was 56.6% (overall phase), compared to 39.5% in the placebo group (P < 0.001) [2]

1. NK1 receptor binding assay (human recombinant): Membrane preparations from cells expressing human NK1 receptors were incubated with [³H]substance P (a selective NK1 ligand) and serial concentrations of Rolapitant HCl in binding buffer at 25°C for 60 minutes. Non-specific binding was determined in the presence of excess unlabeled substance P. Bound radioactivity was measured by filtration and liquid scintillation counting, and the Ki value for Rolapitant HCl was calculated using the Cheng-Prusoff equation (data from three independent experiments, each in triplicate) [1]
2. NK1 receptor binding assay (rat brain cortex): Rat brain cortex membranes were prepared and incubated with [³H]substance P and Rolapitant HCl using the same method as the human recombinant receptor assay. The IC50 value for inhibiting specific [³H]substance P binding was determined from dose-response curves (N=3 independent experiments) [1]
3. Functional calcium mobilization assay: NK1 receptor-expressing cells were loaded with a calcium-sensitive fluorescent dye and incubated with Rolapitant HCl (0.001-100 nM) for 30 minutes, then stimulated with substance P (10 nM). Changes in intracellular calcium concentration were measured by fluorometry, and the IC50 for inhibiting substance P-induced calcium mobilization was calculated (N=4 independent experiments) [1]

Female Mongolian Gerbils (30-60 g; anesthetized by inhalation of an oxygen:isofluorane mixture after 4 h PO or immediately after IV, then injected with 5 μl of 3 pmol solution of GR-73632 via ICV)
0.03, 0.1, 0.3 and 1 mg/kg for PO, 0.3 and 1 mg/kg for IV
PO or IV, single dosage

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1. Ferret cisplatin-induced vomiting model: Male ferrets (1.0-1.5 kg) were randomly divided into vehicle and Rolapitant HCl treatment groups (0.1, 0.3, 1, 3 mg/kg, free base equivalent). Rolapitant HCl was formulated in a vehicle consisting of 0.5% methylcellulose and 0.1% Tween 80 (the hydrochloride salt was dissolved in this vehicle to ensure solubility), administered by oral gavage 1 hour before cisplatin (10 mg/kg, intraperitoneal injection). For intraperitoneal dosing experiments, Rolapitant HCl was dissolved in saline and injected 1 hour before cisplatin. Vomiting episodes and retching were recorded continuously for 72 hours post-cisplatin, with the number of episodes and latency to first vomiting as primary endpoints [1]
2. Ferret substance P-induced vomiting model: Ferrets were administered Rolapitant HCl (3 mg/kg, oral, free base equivalent) or vehicle 1 hour before intravenous injection of substance P (10 μg/kg). Vomiting behavior was observed for 1 hour post-substance P injection, and the number of vomiting episodes was counted to evaluate the antiemetic effect of Rolapitant HCl [1]

In ferrets, rorapitan hydrochloride showed good oral bioavailability (approximately 70% bioavailability based on free base equivalents after a single oral dose of 3 mg/kg), reaching peak plasma concentration (Cmax) 2 hours after administration, with a terminal half-life (t1/2) of approximately 70 hours. Compared to the free base, the hydrochloride form is more water-soluble and more readily absorbed. It can easily cross the blood-brain barrier (BBB) in ferrets, with a brain-to-plasma concentration ratio of 0.8 4 hours after oral administration, confirming its occupancy of central NK1 receptors [1]. In humans, rorapitan hydrochloride (180 mg orally based on free base equivalents) has a relatively long terminal half-life of approximately 180 hours (7.5 days). Rolapitant is primarily metabolized via cytochrome P450 3A4 (CYP3A4) to produce an active metabolite (M19, SCH 99977), which also exhibits NK1 receptor antagonistic activity (Ki = 2.2 nM). Rolapitant hydrochloride is highly bound to human plasma proteins (99.8%), and its metabolism is not affected by co-administration with dexamethasone or granisetron (commonly used antiemetics) [2]

In ferrets, oral doses of up to 30 mg/kg (equivalent to 10 times the effective antiemetic dose, based on free base) of rorapistant hydrochloride did not cause significant changes in body weight, food intake, or behavior, and no significant pathological abnormalities were observed in major organs (brain, liver, kidney, stomach) during autopsy. The hydrochloride form did not increase toxicity compared to the free base [1]. In clinical trials, rorapistant hydrochloride was well tolerated in patients receiving highly emetogenic chemotherapy (HEC). The most common adverse events (AEs) were fatigue (14.7%), constipation (14.1%), headache (10.6%), and diarrhea (9.4%), with no significant difference in the incidence of grade 3/4 adverse events between the rorapistant hydrochloride group (19.7%) and the placebo group (21.5%). Rolapitant hydrochloride does not inhibit or induce major CYP450 enzymes (CYP3A4, CYP2D6, CYP2C9) in humans, and no clinically significant drug interactions have been observed with chemotherapeutic agents (e.g., cisplatin, doxorubicin) or antiemetics (granisetron, dexamethasone) [2]

[1]. Rolapitant (SCH 619734): a potent, selective and orally active neurokininNK1 receptor antagonist with centrally-mediated antiemetic effects inferrets. Pharmacol Biochem Behav. 2012 Jul;102(1):95-100.

[2]. Study of rolapitant, a novel, long-acting, NK-1 receptor antagonist, for the prevention of chemotherapy-induced nausea and vomiting (CINV) due to highly emetogenic chemotherapy (HEC). Support Care Cancer. 2015 Nov;23(11):3281-8.

Rolapitant hydrochloride hydrate is the monohydrate form of rorapistan hydrochloride. It is used to prevent delayed nausea and vomiting associated with initial and repeated courses of emetogenic chemotherapy for cancer. It has antiemetic and neurokinin-1 receptor antagonistic effects. It contains anhydrous rorapistan hydrochloride. Rolapitant hydrochloride is the hydrochloride form of rorapistan, a highly bioavailable, centrally acting, selective neurokinin-1 receptor (NK1 receptor) antagonist with potential antiemetic activity. After oral administration, rorapistan competitively binds to and blocks the activity of NK1 receptors in the central nervous system, thereby inhibiting the binding of the endogenous ligand substance P (SP). This may prevent SP-induced vomiting and chemotherapy-induced nausea and vomiting (CINV). The interaction between substance P and NK1 receptors plays a key role in emetogenic chemotherapy-induced nausea and vomiting. Compared to other NK1 receptor antagonists, rorapistan has a faster onset of action and a longer half-life. See also: Rorapitan (containing active ingredient). Rorapitan hydrochloride (SCH 619734 hydrochloride) is the hydrochloride form of rorapitan, clinically used to treat nausea and vomiting. Rorapitan is a novel, potent, and selective NK1 receptor antagonist with centrally mediated antiemetic activity. Its mechanism of action is to block the binding of substance P (an endogenous ligand of the NK1 receptor) to central and peripheral NK1 receptors, thereby inhibiting the vomiting signal transduction pathway induced by chemotherapy or substance P stimulation. The hydrochloride form of rorapitan has higher water solubility and improves formulation and oral bioavailability compared to the free base [1]. Rorapitan hydrochloride is a long-acting NK1 receptor antagonist approved for the prevention of chemotherapy-induced nausea and vomiting (CINV) caused by highly emetogenic chemotherapy (HEC) and moderately emetogenic chemotherapy (MEC). Its long half-life (about 180 hours) means that it only needs to be taken orally once per chemotherapy cycle (equivalent to 180 mg of free base), which is more convenient than other NK1 antagonists (such as aprepitant, which requires multiple doses). It is formulated into oral tablets for clinical use, taking full advantage of the solubility of the hydrochloride salt[2].

C25H27CLF6N2O2

536.94

554.177

C, 55.92; H, 5.07; Cl, 6.60; F, 21.23; N, 5.22; O, 5.96

914462-92-3

Rolapitant; 552292-08-7; Rolapitant hydrochloride; 858102-79-1

16203739

White to off-white solid powder

7.071

4

10

5

37

731

3

C([C@@]1(NC[C@@]2(CCC(=O)N2)CC1)C1C=CC=CC=1)O[C@@H](C1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1)C.Cl.O

VEWAWEMXVUFANV-PVBCUUEWSA-N

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

(5S,8S)-8-(((R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)methyl)-8-phenyl-1,7-diazaspiro[4.5]decan-2-one hydrochloride

Rolapitant HCl; SCH619734; Rolapitant hydrochloride; SCH-619734; SCH 619734; trade name: Varubi

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

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.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*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).

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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)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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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).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)