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Purity: ≥98%
Ziresovir (known also as AK-0529; RO-0529) is a selective and orally bioavailable inhibitor of respiratory syncytial virus (RSV) fusion (F) protein (RSV F) protein with EC50 of 3 nM. Ziresovir is currently in phase 2 clinical trials. RO-0529 demonstrates single-digit nM EC50 potency against laboratory strains, as well as clinical isolates of RSV in cellular assays, and more than one log viral load reduction in BALB/c mouse model of RSV viral infection. RO-0529 was proven to be a specific RSV F protein inhibitor by identification of drug resistant mutations of D486N, D489V, and D489Y in RSV F protein and the inhibition of RSV F protein-induced cell−cell fusion in cellular assays.
| Targets |
Respiratory syncytial virus (RSV) fusion (F) protein (RSV F) protein (EC50 = 3 nM)
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| ln Vitro |
Ziresovir's efficacies in wild-type (WT) and mutant RSV were found to differ, with corresponding EC50/EC90 values (μM) of 0.003/0.005 for WT, 2.1/10.0 for D486N, and >10/>10 for D489A [1]. The RSV F protein-induced syncytium formation and cell-to-cell fusion process are inhibited by RO-0529 (100 nM; 4 d) [1].
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| ln Vivo |
Ziresovir (12.5 mg/kg, 50 mg/kg; oral; twice daily; 4 days) results in reduced RSV titers in the lungs of mice [1]. Ziresovir (10 mg/kg; oral; single dose) demonstrated good oral exposure and bioavailability in male Wistar-Han rats, with a F(%) of 32% [1]. Ziresovir (150 mg/kg; oral; single dose) exhibits greater tissue distribution to the lungs than plasma in CD-1 mice [1]. Pharmacokinetics of zirisovir in male Wistar-Han rats [1] Dose (mg/kg) AUC0-24h(po) (ng·h/mL) CL (mL/min/kg) T1/2 (iv) (h) Vss ( L/kg) F (%) 2 mg/kg (iv) or 10 mg/kg (po) 906 58 1.2 3.9 32 Pharmacokinetics of Ziresovir in CD-1 mice [ 1] Dose (mg/kg) AUC0-24h(po) ) (μg·h/L) Tissue/Plasma AUC0-24h Ratio (μg·h/L) T1/2 (h) Tmax (h) Cmax (μg/ L) Plasma 8,380 1 1.02 0.25 5090 Lung 72,400 8.6 3.31 1 22700
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| Cell Assay |
CPE assay was performed to assess the protective effects of compounds on cell viability. Plates (96-well) were seeded with 6000 HEp-2 cells per well. Cells were infected the next day with RSV at MOI 0.02 to produce an approximately 90% cytopathic effect after 5 days. Cells were incubated during this period in the presence or absence of serial dilutions of compounds. The viability of cells was assessed after 5 days by CCK-8. Results were expressed as 50% effective concentrations (EC50) and 50% cell cytotoxicity (CC50) values. Plaque reduction assays were carried out by infecting HEp-2 cell monolayers with 0.5 mL of 200 PFU/ml of RSV Long strain per well of a 12-well plate with or without the presence of serial diluted compounds. After 2 h, cells were overlaid with DMEM/F12 containing 4% FBS and 0.55% agarose and compounds. Plates were incubated for 3 days, and cells were then fixed with 4% paraformaldehyde for 6 h. The agarose plugs were removed, and viral plaques were visualized by immunostaining. Cells were blocked with 1× TBS buffer with 1% BSA–0.5% Triton X-100. Plates were then incubated in the presence of a mouse anti-RSV monoclonal antibody (NCL-RSV3; Novocastra) at 1:300 dilution followed by a rabbit anti-mouse horseradish peroxidase-labeled secondary antibody. The plaque staining was developed with 4-chloro-1-naphthol in the presence of hydrogen peroxide, and plaques were counted. [1]
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| Animal Protocol |
Animal/Disease Models: RSV-infected female balb/c (Bagg ALBino) mouse [1]
Doses: 12.5 mg/kg, 50 mg/kg Route of Administration: po (oral gavage); twice a day times; 4-day Experimental Results: Virus titers in the lungs of infected mice were diminished by >1 log unit at dose levels as low as 12.5 mg/kg. Virus titers were diminished to 1.9 log units compared to vehicle at the 50 mg/kg dose. In Vivo Efficacy Study [1] Six-week-old female BALB/c mice were purchased from Jackson Laboratories and fed a standard diet and water ad libitum. Animals were housed in specific-pathogen-free conditions. Animals were anesthetized intraperitoneally with ketamine/xylazine before any intranasal administration. RSV Long strain (5 × 105 plaque-forming units [PFU] for all animal experiments), drugs, and controls were given in 100 μL volumes. Animals were euthanized with CO2, and lungs were harvested. For histopathologic analysis, the left lower lobe of the lung was removed and inflated with 10% formalin. Specimens were fixed, paraffin embedded, stained, and analyzed. |
| ADME/Pharmacokinetics |
The pharmacokinetics of Ziresovir/RO-0529 was studied in mouse, rat, dog, and monkey (Table 7). The in vitro liver microsomal clearance (Mic CL) and hepatocyte clearance (Hep CL) showed a good correlation using microsome preparations of mouse, rat, and dog, respectively. In monkey and human, in vitro liver Mic CL was higher than Hep CL. The in vivo plasma clearance was much higher than liver blood flow in mouse, suggesting the possibility of high blood to plasma ratio or extrahepatic metabolic clearance, such as urinary or biliary excretion. In general, the in vitro Hep CL and in vivo CL correlated well with each other in the rest of species, suggesting that the metabolic clearance is the major clearance pathway in the rat, dog, and monkey. [1]
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| References | |
| Additional Infomation |
Ziresovir is under investigation in clinical trial NCT03699202 (Anti-RSV Study in Chinese Patients (ASCENT)).
Ziresovir (RO-0529, AK0529) is reported here for the first time as a promising respiratory syncytial virus (RSV) fusion (F) protein inhibitor that currently is in phase 2 clinical trials. This article describes the process of RO-0529 as a potent, selective, and orally bioavailable RSV F protein inhibitor and highlights the in vitro and in vivo anti-RSV activities and pharmacokinetics in animal species. RO-0529 demonstrates single-digit nM EC50 potency against laboratory strains, as well as clinical isolates of RSV in cellular assays, and more than one log viral load reduction in BALB/c mouse model of RSV viral infection. RO-0529 was proven to be a specific RSV F protein inhibitor by identification of drug resistant mutations of D486N, D489V, and D489Y in RSV F protein and the inhibition of RSV F protein-induced cell-cell fusion in cellular assays.[1] |
| Molecular Formula |
C22H25N5O3S
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|---|---|
| Molecular Weight |
439.530603170395
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| Exact Mass |
439.167
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| Elemental Analysis |
C, 60.12; H, 5.73; N, 15.93; O, 10.92; S, 7.29
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| CAS # |
1422500-60-4
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| Related CAS # |
2066577-28-2 (hydrate); 1422500-60-4; 2066577-30-6; 2066577-29-3 (acetate);
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| PubChem CID |
71262247
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| Appearance |
White to off-white solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
745.4±70.0 °C at 760 mmHg
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| Flash Point |
404.6±35.7 °C
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| Vapour Pressure |
0.0±2.5 mmHg at 25°C
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| Index of Refraction |
1.679
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| LogP |
0.26
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
31
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| Complexity |
740
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CC1=CC2=C(C=C1)N=C(N=C2NCC3(COC3)N)N4CCS(=O)(=O)C5=CC=CC=C5C4
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| InChi Key |
GAAICKUTDBZCMT-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C22H25N5O3S/c1-15-6-7-18-17(10-15)20(24-12-22(23)13-30-14-22)26-21(25-18)27-8-9-31(28,29)19-5-3-2-4-16(19)11-27/h2-7,10H,8-9,11-14,23H2,1H3,(H,24,25,26)
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| Chemical Name |
N-[(3-aminooxetan-3-yl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine
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| Synonyms |
RO-0529; RO0529; RO 0529; AK0529; Ziresovir; 1422500-60-4; Ziresovir [INN]; XCF42D7AG4; UNII-XCF42D7AG4; ZIRESOVIR [WHO-DD]; AK-0529; AK 0529;
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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 : ~125 mg/mL (~284.39 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.73 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 (4.73 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 (4.73 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2752 mL | 11.3758 mL | 22.7516 mL | |
| 5 mM | 0.4550 mL | 2.2752 mL | 4.5503 mL | |
| 10 mM | 0.2275 mL | 1.1376 mL | 2.2752 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT04788017 | COMPLETED | Drug: Ziresovir Other: Placebo |
Healthy Subjects | Shanghai Ark Biopharmaceutical Co., Ltd. | 2021-03-24 | Phase 1 |
| NCT04231968 | COMPLETED | Drug: AK0529 Drug: Matching placebo of AK0529 |
Respiratory Syncytial Virus Infections | Shanghai Ark Biopharmaceutical Co., Ltd. | 2020-09-22 | Phase 3 |
| NCT03699202 | UNKNOWN STATUS | Drug: AK0529 Drug: Placebo |
Respiratory Syncytial Virus Infections | Shanghai Ark Biopharmaceutical Co., Ltd. | 2019-03-29 | Phase 2 |
| NCT03322800 | COMPLETED | Drug: AK0529 Other: Placebo |
Healthy | Shanghai Ark Biopharmaceutical Co., Ltd. | 2017-10-23 | Phase 1 |
| NCT03400995 | COMPLETED | Drug: AK0529 | Healthy | Shanghai Ark Biopharmaceutical Co., Ltd. | 2018-01-05 | Phase 1 |
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