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| Targets |
HIV; non-nucleoside reverse transcriptase
Ulonivirine targets HIV-1 reverse transcriptase, an enzyme essential for the viral life cycle. As a non-nucleoside inhibitor, it binds to an allosteric site on the enzyme, distinct from the active site where nucleoside analogs bind. This binding induces a conformational change that inhibits the enzyme's polymerase activity, thereby preventing viral replication. It has potent activity against multiple HIV-1 subtypes and common NNRTI-resistant mutant viruses. |
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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].
In vitro, Ulonivirine has high antiviral potency. It demonstrates potent activity against a wide range of HIV-1 clinical isolates, including those resistant to other NNRTIs. Specific EC50 values are not provided in the available sources, but it is described as a next-generation NNRTI with a favorable resistance profile. |
| 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].
In vivo, Ulonivirine has been studied in clinical trials. It is being developed as part of a combination regimen containing islatravir and ulonivirine (MK-8591B). Phase 2b studies have been conducted in treatment-naïve HIV-1 infected adults, showing favorable safety and tolerability. The compound's pharmacokinetic properties support once-weekly oral dosing. |
| Enzyme Assay |
A cell-free assay for Ulonivirine would involve measuring its inhibition of HIV-1 reverse transcriptase activity. In this assay, the enzyme is incubated with a template-primer and nucleotides in the presence of varying concentrations of the compound. The incorporation of nucleotides into the growing DNA strand is measured, and the IC50 is calculated. Specific IC50 values are not provided.
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| Cell Assay |
Cellular assays for Ulonivirine typically involve assessing its antiviral activity in HIV-1-infected cell lines. Cells are infected with HIV-1 and treated with varying concentrations of the compound. Viral replication is measured by quantifying viral p24 antigen or by measuring the production of viral RNA. The compound's potency and selectivity index are determined from these assays.
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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/). In vivo animal experiments for Ulonivirine are not described in the available sources. As a compound that has progressed to clinical trials, preclinical studies in animal models of HIV infection likely contributed to its development. However, specific protocols and data are not provided. |
| ADME/Pharmacokinetics |
Table 44 summarizes the pharmacokinetic characteristics of MK-8507 in plasma, and Figure 1B shows the plasma concentration-time curves. The pharmacokinetic characteristics of MK-8507 are generally dose-dependent. The mean terminal plasma half-life of MK-8507 for each dose group was 56 to 69 hours. [1] Figure 1C shows a scatter plot of weekly trough concentrations (Ctrough, C168hr) versus HIV-1 RNA changes from baseline at 7 days for each dose group. Overall, most data points appear to be located in the flat, maximum-effect portion of the exposure-response curve, but at the 40 mg dose, there is a trend toward decreased responsiveness at the lower end of the C168hr range. [1]
Ulonivirine has pharmacokinetic properties that support once-weekly dosing. It is an orally active compound. Specific parameters such as half-life, bioavailability, and metabolism are not provided in the available sources. It is being developed for oral administration. |
| Toxicity/Toxicokinetics |
MK-8507 was generally well tolerated, and no subjects withdrew from the study due to adverse events (AEs). A total of 10 adverse events occurred in 7 subjects. The most common adverse events were nasopharyngitis (n = 3, 2 moderate, 1 mild) and headache (n = 3, 2 moderate, 1 mild). Of the 10 adverse events, the investigators considered only 3 headaches to be related to the study drug. No clinically significant trends were found in vital signs, electrocardiograms, or laboratory tests. One subject receiving 600 mg of MK-8507 was diagnosed with diffuse large B-cell lymphoma after starting standard antiretroviral therapy (SOC ART); this serious adverse event was considered unrelated to the study drug, and the subject recovered but had sequelae. All other adverse events were mild or moderate and resolved by the end of the study. [1]
Toxicity data for Ulonivirine indicate that it has shown favorable safety and tolerability in Phase 2 studies. Specific adverse effects are not detailed in the available sources. As an investigational drug, its full safety profile is still being established. |
| References | |
| Additional Infomation |
Conclusion: MK-8507 has strong antiviral activity, pharmacokinetic properties and good tolerability, supporting its continued development as part of a complete once-weekly oral regimen for HIV-1 treatment; combination therapy can reduce the emergence of drug-resistant variants. [1]
Ulonivirine (CAS: 1591823-76-5) is a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) for HIV-1. It is also known as MK-8507. The compound has potent in vitro activity against multiple HIV-1 subtypes and NNRTI-resistant mutants. It is being developed for the treatment of HIV-1 infection, with pharmacokinetic properties supporting once-weekly dosing. |
| 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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