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Raltegravir (MK-0518)

HIV-1 integrase inhibitor CAS# 518048-05-0

Raltegravir (MK-0518)

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Chemical structure

Raltegravir (MK-0518)

3D structure

Chemical Properties of Raltegravir (MK-0518)

Cas No. 518048-05-0 SDF Download SDF
PubChem ID 54671008 Appearance Powder
Formula C20H21FN6O5 M.Wt 444.4
Type of Compound N/A Storage Desiccate at -20°C
Synonyms MK-0518
Solubility DMSO : ≥ 100 mg/mL (225.01 mM)
*"≥" means soluble, but saturation unknown.
Chemical Name N-[2-[4-[(4-fluorophenyl)methylcarbamoyl]-5-hydroxy-1-methyl-6-oxopyrimidin-2-yl]propan-2-yl]-5-methyl-1,3,4-oxadiazole-2-carboxamide
SMILES CC1=NN=C(O1)C(=O)NC(C)(C)C2=NC(=C(C(=O)N2C)O)C(=O)NCC3=CC=C(C=C3)F
Standard InChIKey CZFFBEXEKNGXKS-UHFFFAOYSA-N
Standard InChI InChI=1S/C20H21FN6O5/c1-10-25-26-17(32-10)16(30)24-20(2,3)19-23-13(14(28)18(31)27(19)4)15(29)22-9-11-5-7-12(21)8-6-11/h5-8,28H,9H2,1-4H3,(H,22,29)(H,24,30)
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of Raltegravir (MK-0518)

DescriptionRaltegravir is a potent integrase (IN) inhibitor, used to treat HIV infection.In Vitro:PFV IN carrying the S217H substitution is 10-fold less susceptible to Raltegravir with IC50 of 900 nM. PFV IN displays 10% of WT activity and is inhibited by Raltegravir with an IC50 of 200 nM, indicating a appr twofold decrease in susceptibility to the IN strand transfer inhibitor (INSTI) compared with WT IN. S217Q PFV IN is as sensitive to Raltegravir as the WT enzyme[1]. Raltegravir is metabolized by glucuronidation, not hepatically. Raltegravir has potent in vitro activity against HIV-1, with a 95% inhibitory concentration of 31±20 nM, in human T lymphoid cell cultures. Raltegravir is also active against HIV-2 when Raltegravir is tested in CEMx174 cells, with an IC95of 6 nM. Raltegravir metabolism occurs primarily through glucuronidation. Drugs that are strong inducers of the glucuronidation enzyme, UGT1A1, significantly reduce Raltegravir concentrations and should not be used. Raltegravir exhibits weak inhibitory effects on hepatic cytochrome P450 activity. Raltegravir does not induce CYP3A4 RNA expression or CYP3A4-dependent testosterone 6-β-hydroxylase activity[2]. Raltegravir cellular permeativity is reduced in the presence of magnesium and calcium[3]. Raltegravir and related HIV-1 integrase (IN) strand transfer inhibitors (INSTIs efficiently block viral replication[4]. In acutely infected human lymphoid CD4+ T-cell lines MT-4 and CEMx174, SIVmac251 replication is efficiently inhibited by Raltegravir, which shows an EC90 in the low nanomolar range[5].In Vivo:Raltegravir induces viro-immunological improvement of nonhuman primates with progressing SIVmac251 infection. One non-human primate shows an undetectable viral load following Raltegravir monotherapy[5].

References:
[1]. Hare, S., et al., Molecular mechanisms of retroviral integrase inhibition and the evolution of viral resistance. Proc Natl Acad Sci U S A, 2010. 107(46): p. 20057-62. [2]. Hicks C, et al. Raltegravir: the first HIV type 1 integrase inhibitor. Clin Infect Dis. 2009 Apr 1;48(7):931-9. [3]. Moss DM, et al. Divalent metals and pH alter raltegravir disposition in vitro. Antimicrob Agents Chemother. 2012 Jun;56(6):3020-6. [4]. Hare S, et al. Structural and functional analyses of the second-generation integrase strand transfer inhibitor dolutegravir (S/GSK1349572). Mol Pharmacol. 2011 Oct;80(4):565-72. [5]. Lewis, M.G., et al. Response of a simian immunodeficiency virus (SIVmac251) to raltegravir: a basis for a new treatment for simian AIDS and an animal model for studying lentiviral persistence during antiretroviral therapy. Retrovirology, 2010. 7: p. 21. [6]. Xu P, et al. Combined Medication of Antiretroviral Drugs Tenofovir Disoproxil Fumarate, Emtricitabine, and Raltegravir Reduces Neural Progenitor Cell Proliferation In Vivo and In Vitro. J Neuroimmune Pharmacol. 2017 Dec;12(4):682-692.

Protocol

Kinase Assay [1]
For quantitative strand transfer assays, donor DNA substrate is formed by annealing HPLC grade oligonucleotides 5'-GACTCACTATAGGGCACGCGTCAAAATTCCATGACA and 5'-ATTGTCATG GAATTTTGACGCGTGCCCTATAGTGAGTC. Reactions (40 μL) contains 0.75 μM PFV IN, 0.75 μM donor DNA, 4 nM (300 ng) supercoiled pGEM9-Zf(−) target DNA, 125 mM NaCl, 5 mM MgSO4, 4 μM ZnCl2, 10 mM DTT, 0.8% (vol/vol) DMSO, and 25 mM BisTris propane-HCl, pH 7.45. Raltegravir is added at indicated concentrations. Reactions are initiated by addition of 2 μL PFV IN diluted in 150 mM NaCl, 2 mM DTT, and 10 mM Tris-HCl, pH 7.4, and stopped after 1 hour at 37°C by addition of 25 mM EDTA and 0.5% (wt/vol) SDS. Reaction products, deproteinized by digestion with 20 μg proteinase K for 30 minutes at 37°C followed by ethanol precipitation, are separated in 1.5% agarose gels and visualized by staining with ethidium bromide. Integration products are quantified by quantitative real-time PCR, using Platinum SYBR Green qPCR SuperMix and three primers: 5'-CTACTTACTCTAGCTTCCCGGCAAC, 5'-TTCGCCAGTTAATAGTTTGCGCAAC, and 5'-GACTCACTATAGGGCACGCGT. PCR reactions (20 μL) contained 0.5 μM of each primer and 1 μL diluted integration reaction product. Following a 5-min denaturation step at 95°C, 35 cycles are carried out in a CFX96 PCR instrument, using 10 seconds denaturation at 95°C, 30 seconds annealing at 56°C and 1 minutes extension at 68°C. Standard curves are generated using serial dilutions of WT PFV IN reaction in the absence of INSTI.

Cell Assay [5]
Human MT-4 cells are infected for 2 hours with the SIVmac251, HIV-1 (IIIB) and HIV-2 (CDC 77618) stocks at a multiplicity of infection of, approximately, 0.1. Cells are then washed three times in phosphate buffered saline, and suspended at 5 × 105/mL in fresh culture medium (to primary cells 50 units/mL of IL-2 are added) in 96-well plates, in the presence or absence of a range of triplicate raltegravir concentrations (0.0001 μM-1 μM). Untreated infected and mock-infected controls are prepared too, in order to allow comparison of the data derived from the different treatments. Viral cytopathogeniciy in MT-4 cells is quantitated by the methyl tetrazolium (MTT) method (MT-4/MTT assay) when extensive cell death in control virus-infected cell cultures is detectable microscopically as lack of capacity to re-cluster. The capability of MT-4 cells to form clusters after infection. Briefly, clusters are disrupted by pipetting; and, after 2 hours of incubation at 37°C, the formation of new clusters is assessed by light microscopy (100× magnification). Cell culture supernatants are collected for HIV-1 p24 and HIV-2/SIVmac251 p27 core antigen measurement by ELISA. In CEMx174-infected cell cultures, which show a propensity to form syncytia induced by the virus envelope glycoproteins, syncytia are counted, in blinded fashion, by light microscopy for each well at 5 days following infection.

References:
[1]. Hare, S., et al., Molecular mechanisms of retroviral integrase inhibition and the evolution of viral resistance. Proc Natl Acad Sci U S A, 2010. 107(46): p. 20057-62. [2]. Hicks C, et al. Raltegravir: the first HIV type 1 integrase inhibitor. Clin Infect Dis. 2009 Apr 1;48(7):931-9. [3]. Moss DM, et al. Divalent metals and pH alter raltegravir disposition in vitro. Antimicrob Agents Chemother. 2012 Jun;56(6):3020-6. [4]. Hare S, et al. Structural and functional analyses of the second-generation integrase strand transfer inhibitor dolutegravir (S/GSK1349572). Mol Pharmacol. 2011 Oct;80(4):565-72. [5]. Lewis, M.G., et al. Response of a simian immunodeficiency virus (SIVmac251) to raltegravir: a basis for a new treatment for simian AIDS and an animal model for studying lentiviral persistence during antiretroviral therapy. Retrovirology, 2010. 7: p. 21. [6]. Xu P, et al. Combined Medication of Antiretroviral Drugs Tenofovir Disoproxil Fumarate, Emtricitabine, and Raltegravir Reduces Neural Progenitor Cell Proliferation In Vivo and In Vitro. J Neuroimmune Pharmacol. 2017 Dec;12(4):682-692.

Raltegravir (MK-0518) Dilution Calculator

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Preparing Stock Solutions of Raltegravir (MK-0518)

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.2502 mL 11.2511 mL 22.5023 mL 45.0045 mL 56.2556 mL
5 mM 0.45 mL 2.2502 mL 4.5005 mL 9.0009 mL 11.2511 mL
10 mM 0.225 mL 1.1251 mL 2.2502 mL 4.5005 mL 5.6256 mL
50 mM 0.045 mL 0.225 mL 0.45 mL 0.9001 mL 1.1251 mL
100 mM 0.0225 mL 0.1125 mL 0.225 mL 0.45 mL 0.5626 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on Raltegravir (MK-0518)

Raltegravir, formerly named MK-0518, is an HIV-1 integrase strand transfer inhibitor which has been shown to have activity against multidrug-resistant HIV-1 and both CCR5-trophic and CXCR4-trophic HIV-1 in vitro. Structural modifications on these molecules are made in order to maximize potency as HIV-integrase inhibitors against the wild type virus, a selection of mutants, and optimize the selectivity, pharmacokinetic, and metabolic profiles in preclinical species. Raltegravir derives from the evolution of 5,6-dihydroxypyrimidine-4-carboxamides and N-methyl-4-hydroxypyrimidinone-carboxamides. It has been shown to have potent antiretroviral effects, with a mean decrease from baseline in HIV-1 RNA concentrations of about 2 log10 copies per mL after 10 days of monotherapy.

References

Beatriz Grinsztejn, Dr Bach-Yen Nguyen, Christine Katlama, Jose M Gatell, Adriano Lazzarin, Daniel Vittecoq, Charles J Gonzalez, Joshua Chen, Charlotte M Harvey, Robin D Isaacs. Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in treatment-experienced patients with multidrug-resistant virus: a phase II randomised controlled trial. Then Lancet. 2007. 369(9569): 1261–1269.

Vincenzo Summa, Alessia Petrocchi, Fabio Bonelli, Benedetta Crescenzi, Monica Donghi, Marco Ferrara, Fabrizio Fiore, Cristina Gardelli, Odalys Gonzalez Paz, Daria J. Hazuda, Philip Jones, Olaf Kinzel, Ralph Laufer, Edith Monteagudo, Ester Muraglia, Emanuela Nizi, Federica Orvieto, Paola Pace, Giovanna Pescatore, Rita Scarpelli, Kara Stillmock, Marc V. Witmer, Michael Rowley. Discovery of Raltegravir, a Potent, Selective Orally Bioavailable HIV-Integrase Inhibitor for the Treatment of HIV-AIDS Infection. J. Med. Chem., 2008, 51 (18), pp 5843–5855.

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References on Raltegravir (MK-0518)

Quantitative prediction of human clearance guiding the development of Raltegravir (MK-0518, isentress) and related HIV integrase inhibitors.[Pubmed:19144773]

Drug Metab Dispos. 2009 Apr;37(4):873-83.

Human HIV integrase inhibitors are a novel class of antiretroviral drugs that act by blocking incorporation of the proviral DNA into the host cell genome, a crucial step in the life cycle of HIV. In the present work, quantitative methods for prediction of human pharmacokinetics were used to guide the selection of development candidates from a series of dihydroxypyrimidine and N-methylpyrimidinone carboxamide inhibitors of HIV integrase, which are cleared mainly by O-glucuronidation. The pharmacokinetics of 10 drugs from this series was determined in several preclinical species, including rats, dogs, rhesus monkeys, and rabbits, and the in vitro turnover, plasma protein binding, and blood/plasma partition ratio were studied using preparations from both preclinical species and humans. Two clearance prediction methods, based on physiologically based scaling or allometric scaling normalized for differences in microsomal turnover, were used to extrapolate human clearance. For three clinical candidates, including the novel AIDS drug raltegravir (MK-0518, Isentress), oral drug exposure was predicted and compared with that observed in healthy human volunteers. Both scaling methods gave a reasonable correspondence between predicted and observed oral exposure. Prediction errors for the physiologically based method were less than 1.7-fold for two drugs, including raltegravir, and less than 3.5-fold for one drug. The exposures predicted using normalized allometric scaling were within 1.1- to 1.5-fold of observed values for all three compounds. The accuracy of prediction by normalized allometric scaling was similar when using data from either four preclinical species or from rats and dogs only. The prediction methods used may be applicable to other drugs cleared predominantly by glucuronidation.

Quantification of the HIV-integrase inhibitor raltegravir (MK-0518) in human plasma by high-performance liquid chromatography with fluorescence detection.[Pubmed:18434263]

J Chromatogr B Analyt Technol Biomed Life Sci. 2008 May 15;867(2):277-81.

A simple and sensitive HLPC method with fluorescence detection was developed for the accurate determination of the first licensed HIV integrase inhibitor raltegravir in human plasma. A 500-microL plasma sample was spiked with delavirdine as internal standard and subjected to liquid-liquid extraction based on a previously described assay i.e. using hexane/methylene chloride (1:1, v/v%) at pH 4.0. HPLC was performed using a Symmetry Shield RP18 column (150 mm x 4.6 mm), a gradient elution of acetonitrile -0.01% (v/v) triethylamine in water adjusted to pH 3.0 at a flow rate of 1 mL/min and a fluorimetric detector set at 299 and 396 nm as excitation and emission wavelengths, respectively. The retention time was 5.0 min for internal standard and 6.4 min for raltegravir. Calibration curves were linear in the range 5-1000 ng/mL and the accuracy of quality control samples in the range 10-750 ng/mL varied from 98.3 to 99.1% and 98.3 to 101.0% of the nominal concentrations for intra-day and day-to-day analysis, respectively with a precision of 6.3% or less. Among the other antiretroviral drugs which can be given in association to HIV-infected patients, none was found to interfere with internal standard or raltegravir. The described assay was developed for the purpose of therapeutic drug of this HIV integrase inhibitor.

Raltegravir (MK-0518): an integrase inhibitor for the treatment of HIV-1.[Pubmed:18174972]

Drugs Today (Barc). 2007 Dec;43(12):865-77.

In the developed world, access to highly active antiretroviral therapy (HAART) has led to significant reductions in the morbidity and mortality attributed to HIV/AIDS. However, the continual emergence of HIV-1 strains resistant to currently available classes of antiretrovirals highlights the need to develop agents with novel mechanisms of action. Successful completion of the HIV-1 viral life cycle depends in part on the integration of complementary DNA mediated by the enzyme HIV-1 integrase, one of three essential enzymes encoded in the viral genome. The integrase inhibitors have demonstrated the ability to act specifically at the strand transfer step during integration, making HIV-1 integrase a valid and attractive chemotherapeutic target for the treatment of HIV/AIDS. In clinical trials, raltegravir has been shown to be a potent drug with a pharmacokinetic profile that supports a twice-daily dosing schedule. In addition, it has demonstrated a favorable side-effect profile in treatment-naive and -experienced patients and a subset of heavy treatment-experienced patients have been able a achieve virologic suppression with raltegravir as part of combination therapy despite limited treatment options. In October 2007, raltegravir was approved by the U.S. Food and Drug Administration (FDA) for the treatment of HIV-1 as part of combination antiretroviral therapy in treatment-experienced patients-providing an additional option for the management of the HIV-1 infected individual.

Description

Raltegravir is a potent integrase (IN) inhibitor, used to treat HIV infection.

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