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Purity: ≥98%
Tenofovir Alafenamide (formerly also known as TAF and GS-7340) is a novel prodrug of tenofovir, which is a potent reverse transcriptase inhibitor [nucleotide reverse transcriptase inhibitor (NRTIs)], it is used for the treatment of HIV and Hepatitis B. By blocking reverse transcriptase, Tenofovir Alafenamide prevent HIV from multiplying and can reduce the amount of HIV in the body. Tenofovir alafenamide is a prodrug that it is inactive in the parent form, and has to be converted to tenofovir diphosphate (TFV-DP) in vivo.
| Targets |
HIV-1/2 nucleotide reverse transcriptase
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| ln Vitro |
The antiviral activity of tenofovir alafenamide (GS-7340) ranged from 5 to 7 nM in all cell types, although the CC50 for MT-4 and MT-2 cells varied from 4.7 to 42 μM. A panel of HIV-1 and HIV-2 isolates, comprising HIV-1 M group subtypes A to G and group N and O isolates, were used to assess the antiviral activity of TAF. The average TAF EC50 was 3.5 nM, with a range of 0.1 to 12 nM. In contrast, the average EC50 of AZT, the internal control, was 11.8 nM for 29 main HIV-1 strains evaluated in PBMC. TAF's average EC50 for HIV-2 isolates is 1.8 nM, while AZT's average EC50 is 6.4 nM [2].
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| ln Vivo |
When compared to Tenofovir disoproxil fumarate (TDF), Tenofovir alafenamide (GS-7340) hemifumarate, the amidate prodrug of Tenofovir, exhibits better oral bioavailability and plasma stability [1].
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| Enzyme Assay |
Intestinal and Hepatic S9 Stability [1]
GS-7340 was incubated at 10 μM with either dog or human intestinal and hepatic S9 fractions for 120 min at 37 °C in a 96-well plate format. At specified time points following compound addition, samples were quenched with 9 volumes of an aqueous solution containing 25% acetonitrile and 50% methanol. Plates were centrifuged at 3000g for 30 min, and 10 μL of the resulting solution was analyzed by LC–MS/MS. Data (analyte to internal standard peak area ratio) were plotted on a semi log scale and fitted using an exponential fit. Assuming first order kinetics, the half-life and rate of metabolism were determined. Predicted hepatic extraction was calculated from the half-life by reported methods using the well-stirred model for hepatic clearance. |
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| Cell Assay |
Caco-2 Permeability [1]
Bidirectional permeability studies were done using confluent monolayers of the human colon carcinoma cell line caco-2 seeded in 12-well plates as previously reported. The effects of either concentration (10, 100, or 1,000 μM) or efflux transporter inhibition on the permeation of GS-7340 were studied. Effect of the inhibition of efflux transporters including P-glycoprotein (Pgp) was assessed following a 30 min preincubation of cell monolayers with 10 μM cyclosporin A (CsA) in transport buffer to allow for saturation of transporter binding sites. Following preincubation, fresh assay buffer containing CsA and GS-7340 was added and the assay was started. Each determination was performed in duplicate, and the permeability of control compounds (atenolol, propranolol, and digoxin) was determined to meet acceptance criteria for each batch of assay plates. |
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| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
As compared to the parent molecule, [tenofovir], tenofovir alafenamide presents a lipophilic group that masks the negative charge of the parent moiety which improves its oral bioavailability. Tenofovir alafenamide is highly stable in plasma and, after administration of this prodrug, there is a low concentration of tenofovir in plasma. After oral administration, tenofovir alafenamide is rapidly absorbed by the gut. When a single dose is administered, a peak concentration of 16 ng/ml of the parent compound, corresponding to about 73% of the dose, is observed after 2 hours with an AUC of 270 ng\*h/mL. Once inside the body, tenofovir alafenamide enters hepatocytes by passive diffusion regulated by the organic anion transporters 1B1 and 1B3 for its activation. Administration of tenofovir alafenamide concomitantly with a high-fat meal results in an increase of about 65% in its internal exposure. Tenofovir alafenamide has been registered to present a bile elimination that corresponds to 47% of the administered dose and a renal elimination the represents about 36%. From the recovered dose in urine, about 75% is represented as unchanged [tenofovir] followed by uric acid and a small dose of tenofovir alafenamide. On the other hand, in feces, 99% of the recovered dose corresponds to tenofovir. In clinical trials, the reported volume of distribution of tenofovir alafenamide was higher than 100 L. The reported clearance rate of tenofovir alafenamide is 117 L/h. In patients with severe renal impairment, this value can be decreased by 50%, reporting a rate of 61.7 L/h. Metabolism / Metabolites To be activated, tenofovir alafenamide is required to be hydrolyzed to the parent compound [tenofovir] by the activity of cathepsin A or carboxylesterase 1. Tenofovir alafenamide presents significant plasma stability and hence, its activation is performed inside the target cells. After activation, tenofovir is further processed and after 1-2 days, it is detected in plasma almost completely transformed to uric acid. Biological Half-Life The reported half-life for tenofovir alafenamide is of 0.51 hours. |
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| Toxicity/Toxicokinetics |
Protein Binding
Tenofovir alafenamide is reported to bind to plasma proteins and _ex vivo_ studies have registered that approximately 80% of the administered dose of this drug is presented in a bound state. |
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| References |
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| Additional Infomation |
Pharmacodynamics
Tenofovir alafenamide has been shown to be a potent inhibitor of hepatitis B viral replication. Tenofovir alafenamide presents a better renal tolerance when compared with the counterpart [tenofovir disoproxil]. This improved safety profile seems to be related to a lower plasma concentration of tenofovir. In clinical trials, tenofovir alafenamide was shown to present 5-fold more potent antiviral activity against HIV-1 when compared to tenofovir disoproxil. |
| Molecular Formula |
C21H29N6O5P
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| Molecular Weight |
476.47
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| Exact Mass |
476.193
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| Elemental Analysis |
C, 52.94; H, 6.13; N, 17.64; O, 16.79; P, 6.50
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| CAS # |
379270-37-8
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| Related CAS # |
Tenofovir alafenamide fumarate;379270-38-9;Tenofovir alafenamide hemifumarate;1392275-56-7
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| PubChem CID |
9574768
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| Appearance |
White to off-white solid
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| Density |
1.39±0.1 g/cm3
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| Boiling Point |
640.4±65.0 °C at 760 mmHg
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| Melting Point |
104-107 ºC
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| Flash Point |
341.1±34.3 °C
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| Vapour Pressure |
0.0±1.9 mmHg at 25°C
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| Index of Refraction |
1.630
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| LogP |
2.2
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
12
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| Heavy Atom Count |
33
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| Complexity |
680
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| Defined Atom Stereocenter Count |
3
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| SMILES |
[P@](C([H])([H])OC([H])(C([H])([H])[H])C([H])([H])N1C([H])=NC2=C(N([H])[H])N=C([H])N=C12)(N([H])C([H])(C(=O)OC([H])(C([H])([H])[H])C([H])([H])[H])C([H])([H])[H])(=O)OC1C([H])=C([H])C([H])=C([H])C=1[H]
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| InChi Key |
LDEKQSIMHVQZJK-AZFZMOAFSA-N
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| InChi Code |
InChI=1S/C21H29N6O5P/c1-14(2)31-21(28)16(4)26-33(29,32-17-8-6-5-7-9-17)13-30-15(3)10-27-12-25-18-19(22)23-11-24-20(18)27/h5-9,11-12,14-16H,10,13H2,1-4H3,(H,26,29)(H2,22,23,24)/t15-,16+,33?/m1/s1
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| Chemical Name |
(S)-isopropyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl)amino)propanoate
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| Synonyms |
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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 |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.37 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 20.8 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: ≥ 2.08 mg/mL (4.37 mM) (saturation unknown) 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. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. 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. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (4.37 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 40 mg/mL (83.95 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0988 mL | 10.4938 mL | 20.9877 mL | |
| 5 mM | 0.4198 mL | 2.0988 mL | 4.1975 mL | |
| 10 mM | 0.2099 mL | 1.0494 mL | 2.0988 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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