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Ulonivirine (MK-8507; MK8507) is a novel potent and orally bioactive NNRTI/non-nucleoside reverse transcriptase inhibitor with antiviral activity. Ulonivirine is currently being developed in clinical trials for the treatment of HIV-1 infection. MK-8507 has high antiviral potency in vitro and pharmacokinetic (PK) properties that support once-weekly dosing.
| Targets |
HIV; non-nucleoside reverse transcriptase
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|---|---|
| ln Vitro |
MK-8507 is a novel HIV-1 non-nucleoside reverse transcriptase inhibitor being developed for treatment of HIV-1 infection. MK-8507 has high antiviral potency in vitro and pharmacokinetic (PK) properties that support once-weekly dosing[1].
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| ln Vivo |
A total of 18 participants were enrolled (6 per panel). The mean 7-day postdose HIV-1 RNA reduction ranged from ∼1.2 to ∼1.5 log10 copies/mL across the doses assessed. One patient had a viral rebound associated with emergence of an F227C reverse transcriptase variant (per chain-termination method sequencing) 14 days postdose; this variant was found in a second participant by ultra-deep sequencing as an emerging minority variant. MK-8507 PKs were generally dose-proportional and similar to observations in participants without HIV-1 infection in prior studies; mean MK-8507 half life was 56-69 hours in this study. MK-8507 was generally well tolerated at all doses[1].
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| Animal Protocol |
In 3 sequential panels, participants aged 18-60 years with baseline plasma HIV-1 RNA ≥10,000 copies/mL and CD4+ T-cell count >200/mm3 received a single oral dose of 40, 80, or 600 mg MK-8507 in the fasted state. Participants were assessed for HIV-1 RNA for at least 7 days, PKs for 14 days, and safety and tolerability for 21 days postdose.[1]
Pharmacokinetics[1] MK-8507 in plasma was extracted by protein precipitation and analyzed by Merck & Co., Inc., (West Point, PA) using liquid–liquid extraction for analyte isolation followed by liquid chromatographic-tandem mass spectrometric detection. The lower limit of quantitation was 1.0 ng/mL (2.03 nM) with a linear calibration range from 1.0 to 1000 ng/mL. All PK parameter values were calculated by noncompartmental analysis using the software Phoenix WinNonlin Professional (Version 6.3; Certara, Princeton, NJ). Maximum plasma concentration (Cmax), plasma concentration at 168 hours (C168hr), and time to maximum plasma concentration (Tmax) were generated from the observed plasma concentration time data. Area under the concentration–time curve from time 0 to infinity (AUC0–∞) and time 0–168 hours (AUC0–168) were calculated using the linear trapezoidal method for ascending concentrations and the log trapezoidal method for descending concentrations (linear-up/log-down). The PK/pharmacodynamic (PD) relationship was assessed by examining the correlation between MK-8507 C168hr and the reduction in plasma HIV-1 RNA levels from baseline at 168 hours (7 days) postdose with a nonlinear least squares approach using an Emax model. The nonlinear least squares analysis was conducted using R (version 3.6.3; R Foundation for Statistical Computing, Vienna, Austria. URL https://www.R-project.org/). |
| ADME/Pharmacokinetics |
Plasma MK-8507 PKs are summarized in Table Table44 and plasma concentration–time profiles are shown in Figure Figure1B.1B. MK-8507 PKs were generally dose-proportional. The mean terminal plasma half-life of MK-8507 ranged from 56 to 69 hours across dose groups.[1]
A scatterplot of individual weekly Ctrough (C168hr) and HIV-1 RNA change from baseline at 7 days is shown in Figure Figure1C.1C. In general, most data points seem to be on the flat, maximal-effect portion of the exposure–response relationship, with a trend toward decreased response at the lower end of the C168hr range at the 40 mg dose.[1] |
| Toxicity/Toxicokinetics |
MK-8507 was generally well tolerated and no participant discontinued the study because of an AE. Seven participants experienced a total of 10 AEs. The most common were nasopharyngitis (n = 3, 2 moderate and 1 mild) and headache (n = 3, 2 moderate and 1 mild). Of the 10 AEs, only the 3 events of headache were considered by the investigator to be related to the study drug. There were no clinically meaningful trends in vital signs, electrocardiograms, or laboratory tests. One participant who received 600 mg MK-8507 was diagnosed with diffuse large B cell lymphoma after having started SOC ART; this serious AE was not considered related to study drug and the participant recovered with sequelae. All other AEs were mild or moderate in intensity and resolved by the end of the study.[1]
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| References | |
| Additional Infomation |
Conclusions: The robust antiviral activity, PK, and tolerability of MK-8507 support its continued development as part of a complete once weekly oral regimen for HIV-1 treatment; combination therapy could mitigate the emergence of resistance-associated variants.[1]
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| Molecular Formula |
C18H8CLF6N5O3
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|---|---|
| Molecular Weight |
491.731243133545
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| Exact Mass |
491.021
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| Elemental Analysis |
C, 43.97; H, 1.64; Cl, 7.21; F, 23.18; N, 14.24; O, 9.76
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| CAS # |
1591823-76-5
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| PubChem CID |
73505111
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| Appearance |
White to light yellow solid powder
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| LogP |
2.7
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
12
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
33
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| Complexity |
1020
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C(#N)C1=CC(OC2C(=O)N(CC3=NNC(=O)C(C(F)(F)F)=C3)C=NC=2C(F)(F)F)=CC(Cl)=C1
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| InChi Key |
YSFHLBYWQCLYIY-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C18H8ClF6N5O3/c19-9-1-8(5-26)2-11(3-9)33-13-14(18(23,24)25)27-7-30(16(13)32)6-10-4-12(17(20,21)22)15(31)29-28-10/h1-4,7H,6H2,(H,29,31)
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| Chemical Name |
3-chloro-5-{[6-oxo-1-{[6-oxo-5-(trifluoromethyl)-1,6- dihydropyridazin-3-yl]methyl}-4-(trifluoromethyl)-1,6- dihydropyrimidin-5-yl]oxy}benzonitrile
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| Synonyms |
MK8507; MK-8507; Ulonivirine; 1591823-76-5; 4NS011EGKZ; 3-chloro-5-((6-oxo-1-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)methyl)-4-(trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile; UNII-4NS011EGKZ; MK8507; WHO 12037; MK 8507
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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 |
| 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 : ~250 mg/mL (~508.41 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.08 mg/mL (4.23 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
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 (4.23 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 20.8 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 | 2.0336 mL | 10.1682 mL | 20.3364 mL | |
| 5 mM | 0.4067 mL | 2.0336 mL | 4.0673 mL | |
| 10 mM | 0.2034 mL | 1.0168 mL | 2.0336 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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