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Purity: ≥98%
Letermovir (formerly MK-8828; MK8828; AIC-246; AIC246; trade name: Prevymis) is a potent anti-cytomegalovirus (CMV) / antiviral drug approved on 11/8/2017 by FDA to prevent infection after bone marrow transplant. It acts by targeting the pUL56 (amino acid 230-370) subunit of the viral terminase complex and remaining active against virus resistant to DNA polymerase inhibitors. Letermovir has been tested in CMV infected patients with allogeneic stem cell transplants and may also be useful for other patients with a compromised immune system such as those with organ transplants or HIV infections.
| ln Vitro |
Letermovir (formerly known as MK-8828 and AIC-246; trade name: Prevymis) is a new potent anticytomegalovirus drug in clinical development. On 11/8/2017, Letermovir was approved by FDA to prevent infection after bone marrow transplant. Despite modern prevention and treatment strategies, human cytomegalovirus (HCMV) remains a common opportunistic pathogen associated with serious morbidity and mortality in immunocompromised individuals, such as transplant recipients and AIDS patients. All drugs currently licensed for the treatment of HCMV infection target the viral DNA polymerase and are associated with severe toxicity issues and the emergence of drug resistance.
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| ln Vivo |
Letermovir (10-100 mg/kg/day, p.o.) leads to a dose-dependent reduction of the HCMV titer in transplanted cells compared to that of the placebo-treated control group using the mouse xenograft model
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| Enzyme Assay |
AIC246 has consistent antiviral efficacy, and there is remarkable selectivity of AIC246 for human cytomegaloviruses. AD169 mutant strains and designated rAIC246-1 and rAIC246-2 are highly resistant to Letermovir (AIC246), with EC50s of 5.6 nM, 1.24 μM, 0.37 μM, respectively. Letermovir inhibits HCMV replication through a specific antiviral mechanism that involves the viral gene product UL56. Letermovir inhibits HCMV replication in cell culture by interfering with the proper cleavage/packaging of HCMV progeny DNA[2]. Letermovir inhibits the current gold standard GCV by more than 400-fold with respect to EC50s (mean, 4.5 nM versus 2 μM) and by more than 2,000-fold with respect to EC90 values (mean, 6.1 nM versus 14.5 μM)[3]. Letermovir in conbination with anti-HCMV drugs causes additive antiviral effects, but there is no interaction between letermovir and anti-HIV drugs.
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| Cell Assay |
Briefly, 5×103 AD169-infected NHDF cells/well are seeded into the wells of 30 96-well microtiter plates. The infection is allowed to proceed under the exposure of 50 nM AIC246 (10×EC50) until a CPE developed in one or more of the compound-treated wells (indicative of resistant virus breakthrough). Noninfected and nontreated cells serve as controls on each plate. Mutant virus amplification is accomplwashed after cultures achieved maximum CPE by the passage of cell-free supernatant virus in the presence of 50 nM AIC246. The resultant AIC246-resistant progeny virus mutants are plaque purified three times by limiting dilutions in the presence of AIC246. The stability of resistance is tested by serially passaging plaque-purified viruses without selective pressure (8 to 10 times).
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| Animal Protocol |
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| References |
| Molecular Formula |
C29H28F4N4O4
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| Molecular Weight |
572.56
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| Exact Mass |
572.20
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| Elemental Analysis |
C, 60.84; H, 4.93; F, 13.27; N, 9.79; O, 11.18
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| CAS # |
917389-32-3
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| Related CAS # |
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| Appearance |
Solid powder
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| SMILES |
FC1=C([H])C([H])=C([H])C2=C1N=C(N(C1C([H])=C(C(F)(F)F)C([H])=C([H])C=1OC([H])([H])[H])[C@@]2([H])C([H])([H])C(=O)O[H])N1C([H])([H])C([H])([H])N(C2C([H])=C([H])C([H])=C(C=2[H])OC([H])([H])[H])C([H])([H])C1([H])[H]
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| InChi Key |
FWYSMLBETOMXAG-QHCPKHFHSA-N
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| InChi Code |
InChI=1S/C29H28F4N4O4/c1-40-20-6-3-5-19(16-20)35-11-13-36(14-12-35)28-34-27-21(7-4-8-22(27)30)23(17-26(38)39)37(28)24-15-18(29(31,32)33)9-10-25(24)41-2/h3-10,15-16,23H,11-14,17H2,1-2H3,(H,38,39)/t23-/m0/s1
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| Chemical Name |
(S)-2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-(4-(3-methoxyphenyl)piperazin-1-yl)-3,4-dihydroquinazolin-4-yl)acetic acid
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| Synonyms |
MK-8828; MK 8828; MK8828; AIC-246; AIC 246; AIC246; Letermovir; Prevymis
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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) |
DMSO : ~100 mg/mL ( ~174.65 mM )
Ethanol : ~100 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 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 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 (4.37 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 25.0 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: ≥ 2.5 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: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 2.5 mg/mL (4.37 mM) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7465 mL | 8.7327 mL | 17.4654 mL | |
| 5 mM | 0.3493 mL | 1.7465 mL | 3.4931 mL | |
| 10 mM | 0.1747 mL | 0.8733 mL | 1.7465 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.
Anti-HCMV activities and cytotoxicities for letermovir in combination with GCV (A), CDV (B), FOS (C), and ACV (D).Antimicrob Agents Chemother.2015;59(6):3140-8. |
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Efficacy analysis of two-drug combinations by use of the Bliss independence model.Antimicrob Agents Chemother.2015;59(6):3140-8. |
(A) Effects of therapeutic drug concentrations of selected anti-HIV drugs on the letermovir EC50value for inhibition of HCMV replication. (B) Effects of a clinically relevant letermovir dose on the EC50values of the indicated anti-HIV drugs for inhibition of HIV-1 replication.Antimicrob Agents Chemother.2015;59(6):3140-8. |
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