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Purity: ≥98%
Aprepitant (formerly known as MK-0869; MK-869; L-754030; trade name: Emend) is a novel, selective and high-affinity small molecule antagonist of neurokinin 1 receptor with a Kd of 86 pM. Apepitant is able to selectively bind to the human substance P/neurokinin 1 receptor in the central nervous system (CNS) by crossing the blood brain barrier. This inhibits the receptor's ability to bind endogenous substance P and substance P-induced emesis. Aprepitant exhibits negligible or absent affinity towards corticosteroid, dopamine, and serotonin type 3 (5-HT3) receptors.
| Targets |
G-CSF; IL-6; IL-8; TNFα; Neurokinin-1 receptor( IC50 = 0.1 nM)
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| ln Vitro |
Aprepitant decreases metabolic activity with an estimated IC50 value of 20 µM. Aprepitant causes G1 cell cycle arrest and inhibition of cell growth. In Nalm-6 cells, apropitant strongly induces apoptosis, which is mediated by activating caspase-3. Pro-apoptotic p53 target gene expression and p53 accumulation are induced by aprepitant (20 µM)[2]. In a dose-dependent manner, aprepitant (1, 5, 10 µM) inhibits HIV infection in MDM from HIV-negative individuals who are depressed and those who are not. Apreciant's IC50 value is approximately 5 μM, while its IC90 value is 10 μM[4].
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| ln Vivo |
Aprepitant inhibits the upregulation of NK-1R expression brought on by B. burgdorferi infection of NHP in vivo. B. burgdorferi-induced elevations in CCL2 protein levels in NHP CSF are inhibited by aprepitant treatment. Aprepitant treatment inhibits B. burgdorferi-induced increases in the mRNA expression of CCL2 and CXCL13 in the NHPs' dorsal root ganglia as well as CCL2, CXCL13, IL-17A, and IL-6 in the NHPs' spinal cord. The reductions in astrocyte activity/numbers caused by B. burgdorferi infection are lessened by aparepitant treatment[1]. In mice, the locomotor activation and CPP expression induced by AMPH and cocaine are significantly reduced by aparepitant (10 mg/kg, i.p.). Significant CPP, conditioned place aversion, locomotor activation, or suppression are not induced by appetizing substances[3]. Comparing treated with aparepitant (125 mg/day, p.o.), the levels of viral RNA in plasma are reduced by 1 log[4].
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| Cell Assay |
Appetitant's inhibitory effect on Nalm-6 cells' metabolic activity is measured by the viable cells' uptake of thiazolyl blue tetrazolium bromide (MTT). At a density of 5000 cells per well, cells are plated onto 96-well plates. Following 24–36–48 hours of aprepitant treatment at 5, 10, 15, 20, and 30 µM, the cells are then incubated for 3 hours at 37°C with 100 μL of MTT (0.5 mg/mL). The control group consists of untreated cells. An ELISA reader is used to measure the optical densitometry at a wavelength of 578 nm after solubilizing the precipitated formazan with 100 μL of DMSO.
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| Animal Protocol |
Fifteen rhesus macaques undergo anesthesia and are intrathecally injected with 1×108 live spirochetes into the cisterna magna. The remaining five macaques remain uninfected and are given 1 mL of RPMI 1640 medium after a corresponding amount of CSF is removed. A positive culture from at least a necropsy tissue sample indicates the establishment of an in vivo B. burgdorferi infection. The first group of animals, which were divided into two control groups (one receiving aprepitant treatment), two infected groups receiving no treatment, and two infected groups receiving aprepitant treatment, were all subjected to a two-week study. The second group of animals, which consists of five infected and untreated animals, four infected animals treated with aprepitant, and three control animals, one of which is treated with aprepitant, are all studied for four weeks. Apepitant is given to animals orally twice a day at an average dose of 28 ± 6 mg/kg, and medication treatments begin two days prior to inoculation. These dosages align with typical veterinary regimens for the selected medications in NHP, and the 4-week study period avoids the development of neural pathology, which happens eight weeks after B. burgdorferi infection.
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| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
The mean absolute oral bioavailability of aprepitant is approximately 60 to 65%. Aprepitant is eliminated primarily by metabolism; aprepitant is not renally excreted. Aprepitant is excreted in the milk of rats. It is not known whether this drug is excreted in human milk. 70 L Apparent plasma cl=62-90 mL/min Metabolism / Metabolites Aprepitant primarily undergoes CYP3A4-mediated metabolism, as well as minor metabolism mediated by CYP1A2 and CYP2C19. About seven metabolites of aprepitant have been identified in human plasma, which all retain weak pharmacological activity. Aprepitant has known human metabolites that include 5-oxo-1,4-dihydro-1,2,4-triazole-3-carbaldehyde, 1-[3,5-bis(trifluoromethyl)phenyl]ethanone, 5-{[(2S,3S)-3-(4-fluorophenyl)-2-hydroxymorpholin-4-yl]methyl}-2,4-dihydro-1,2,4-triazol-3-one, and (2R,3S)-2-((R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-3-(4-fluorophenyl)morpholine. Biological Half-Life 9-13 hours |
| Toxicity/Toxicokinetics |
Hepatotoxicity
In preregistration clinical trials of aprepitant, serum aminotransferase elevations occurred in 6% of treated patients compared to 4.3% in controls receiving cancer chemotherapy. The aminotransferase elevations were transient, mild-to-moderate in severity, and not associated with symptoms or jaundice. There have been no convincing cases of clinically apparent liver injury attributable to aprepitant or fosaprepitant published in the literature and thus, significant liver injury from their use must be exceedingly rare if it occurs at all. Likelihood score: E (unlikely causes of clinically apparent liver injury). Protein Binding Protein binding is reported to be >95%. |
| References |
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| Additional Infomation |
Pharmacodynamics
Aprepitant, an antiemetic, is a substance P/neurokinin 1 (NK1) receptor antagonist which, in combination with other antiemetic agents, is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy. Aprepitant is a selective high-affinity antagonist of human substance P/neurokinin 1 (NK1) receptors. Aprepitant has little or no affinity for serotonin (5-HT3), dopamine, and corticosteroid receptors, the targets of existing therapies for chemotherapy-induced nausea and vomiting (CI NV). |
| Molecular Formula |
C23H21F7N4O3
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|---|---|
| Molecular Weight |
534.426669836044
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| Exact Mass |
534.15
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| Elemental Analysis |
C, 51.69; H, 3.96; F, 24.88; N, 10.48; O, 8.98
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| CAS # |
170729-80-3
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| PubChem CID |
135413536
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| Appearance |
White solid powder
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| Density |
1.5±0.1 g/cm3
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| Melting Point |
75-76 °C(lit.)
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| Index of Refraction |
1.564
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| LogP |
4.23
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
12
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
37
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| Complexity |
810
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| Defined Atom Stereocenter Count |
3
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| SMILES |
O=C1NC(CN2[C@H]([C@@H](O[C@@H](C3=CC(C(F)(F)F)=CC(C(F)(F)F)=C3)C)OCC2)C4=CC=C(F)C=C4)=NN1
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| InChi Key |
ATALOFNDEOCMKK-OITMNORJSA-N
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| InChi Code |
InChI=1S/C23H21F7N4O3/c1-12(14-8-15(22(25,26)27)10-16(9-14)23(28,29)30)37-20-19(13-2-4-17(24)5-3-13)34(6-7-36-20)11-18-31-21(35)33-32-18/h2-5,8-10,12,19-20H,6-7,11H2,1H3,(H2,31,32,33,35)/t12-,19+,20-/m1/s1
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| Chemical Name |
3-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholin-4-yl]methyl]-1,4-dihydro-1,2,4-triazol-5-one
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| Synonyms |
L754030; L-754030; L 754030; MK0869; MK 0869; MK-0869; ONO7436; ONO-7436; ONO 7436; Emend; Aponvie; Cinvanti; L-754030; Aprepitant; trade name: Emend
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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: This product requires protection from light (avoid light exposure) during transportation and storage. |
| 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: ~107 mg/mL (~200.2 mM)
Ethanol: ~15 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.68 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 25.0 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: ≥ 2.5 mg/mL (4.68 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8712 mL | 9.3558 mL | 18.7115 mL | |
| 5 mM | 0.3742 mL | 1.8712 mL | 3.7423 mL | |
| 10 mM | 0.1871 mL | 0.9356 mL | 1.8712 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.
Comparison of Adding EMEND to PONV/PDNV Treatment Regimen
CTID: NCT01186029
Phase: N/A Status: Withdrawn
Date: 2024-08-30
Aprepitant treatment preventsB. burgdorferi-induced increases in CCL2, CXCL13, IL-17A, and IL-6 mRNA expression in the spinal cord of NHPs.J Neuroinflammation.2017 Feb 15;14(1):37. |
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Aprepitant treatment preventsB. burgdorferi-induced increases in CCL2 and CXCL13 mRNA expression in the dorsal root ganglia of NHPs. Rhesus macaques were uninfected (n = 5 animals) or infected intrathecally withB. burgdorferi(Bb, 1 × 108bacteria;n = 15), and were untreated (n = 7) or treated with aprepitant (Ap,n = 8) for 2 (a) or 4 (b,c) weeks.The level of expression of mRNA encoding CXCL13 (a,b) and CCL2 (c) in the dorsal root ganglia was determined by qPCR. Data is expressed as the mean ± SD and asterisks indicate statistically significant differences between the untreated and treated groups (p J Neuroinflammation.2017 Feb 15;14(1):37. |
Aprepitant treatment preventsB. burgdorferi-induced increases in CCL2 protein levels in the CSF of NHPs.Rhesus macaques were uninfected (n = 5 animals) or infected intrathecally withB. burgdorferi(Bb, 1 × 108bacteria;n = 15) and were untreated (n = 7) or treated with aprepitant (Ap,n = 8) for 2 (a) or 4 (b) weeks.
Aprepitant treatment attenuatesB. burgdorferiinfection-induced reductions in astrocyte activity/numbers. Rhesus macaques were uninfected orx infected intrathecally withB. burgdorferi(Bb, 1 × 108bacteria) and were untreated or treated with aprepitant (Ap) for 2 or 4weeks prior to euthanasia.J Neuroinflammation.2017 Feb 15;14(1):37. |
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