| Size | Price | Stock | Qty |
|---|---|---|---|
| 5mg |
|
||
| 10mg |
|
||
| 25mg |
|
||
| 50mg |
|
||
| Other Sizes |
Purity: ≥98%
Rilematovir (JNJ678; JNJ-53718678; JNJ-678; JNJ53718678) is a novel, oral and potent fusion protein inhibitor with antiviral activity. It is currently in clinical trials for treating respiratory syncytial virus (RSV). Oral treatment of neonatal lambs with JNJ-53718678, or with an equally active close analog, efficiently inhibits established acute lower respiratory tract infection in the animals, even when treatment is delayed until external signs of respiratory syncytial virus illness have become visible. Together, these data suggest that JNJ-53718678 is a promising candidate for further development as a potential therapeutic in patients at risk to develop respiratory syncytial virus acute lower respiratory tract infection.Respiratory syncytial virus causes lung infections in children, immunocompromised adults, and in the elderly.
| Targets |
Fusion protein[1]
Currently undergoing clinical evaluation in infants hospitalized for respiratory syncytial virus (RSV) infection is rilematovir, a small-molecule RSV fusion inhibitor. The prefusion conformation of the RSV F protein is where rimetavir binds. Rilematovir exhibits minimal cytotoxicity and strong antiviral activity. Apart from its efficacy against the RSV A2 strain, Rilematovir exhibits strong activity against several RSV strains belonging to both the A and B subtypes. HeLa cells are used in an RSV infection assay, and the EC50 is 460 pM[1]. |
|---|---|
| ln Vitro |
Currently undergoing clinical evaluation in infants hospitalized for respiratory syncytial virus (RSV) infection is rilematovir, a small-molecule RSV fusion inhibitor. The prefusion conformation of the RSV F protein is where rimetavir binds. Rilematovir exhibits minimal cytotoxicity and strong antiviral activity. Apart from its efficacy against the RSV A2 strain, Rilematovir exhibits strong activity against several RSV strains belonging to both the A and B subtypes. HeLa cells are used in an RSV infection assay, and the EC50 is 460 pM[1].
JNJ-53718678 exhibited potent antiviral activity against RSV A2 strain in HeLa cells with an average EC50 of 460 pM. The selectivity index (CC50/EC50) was >10^5.[1] The compound was also highly active against multiple RSV strains from both A and B subtypes.[1] In air-liquid interface cultures of human bronchial epithelial cells (HBECs), the EC50 was 1.2 nM when administered at the time of infection.[1] When administered 6 or 24 hours post-infection in HBECs at 100 nM, viral replication and viral titer were significantly reduced by approximately 1.3 log10.[1] JNJ-53718678 showed no activity against other paramyxoviruses, pneumoviruses (including human metapneumovirus), or viruses from other families.[1] Viral escape mutations selected against JNJ-53718678 were L141W in the fusion peptide and D489Y in the heptad repeat B (HRB) motif of RSV F protein, confirming target specificity.[1] |
| ln Vivo |
Neonatal lambs treated orally with Rilematovir or a close analog that is equally active effectively suppresses established acute lower respiratory tract infections in the animals, even in cases where treatment is postponed until the animals exhibit outward symptoms of respiratory syncytial virus illness[1].
Oral prophylactic treatment with a single dose of JNJ-53718678 (100 mg/kg) in cotton rats 1 hour before RSV infection resulted in an average 100-fold decrease in lung infectious viral titer and reduced viral RNA production.[1] Therapeutic treatment of cotton rats with multiple once-daily doses of 40 mg/kg starting 24 hours post-infection led to a significant 1.5 log10 decrease in RSV titer in bronchoalveolar lavage fluid (BALF) and lung tissue.[1] In neonatal lambs, once-daily oral treatment with 25 mg/kg JNJ-53718678 starting 1 day post-infection nearly completely eradicated infectious RSV titer and viral RNA in BALF and lung tissue by day 6, and prevented gross and microscopic RSV-induced lung lesions.[1] Treatment with a close analog (JNJ-49214698, 25 mg/kg) starting 3 days post-infection in lambs resulted in an almost 99% reduction in infectious viral titer and a profound reduction in lung pathology compared to vehicle controls.[1] In RSV-infected BALB/c mice, a single 40 mg/kg prophylactic dose of JNJ-53718678 significantly reduced lung viral titer, pro-inflammatory cytokines/chemokines, and influx of immune cells (e.g., ~5.5-fold reduction in neutrophils).[1] |
| Enzyme Assay |
Isothermal titration calorimetry (ITC) analysis was performed to characterize the binding of JNJ-53718678 to a prefusion-stabilized RSV F protein (DS-Cav1). The compound bound tightly with an equilibrium dissociation constant (KD) of 7.4 nM. Binding was enthalpically driven with a stoichiometry of one inhibitor per trimer. No binding was detected to post-fusion RSV F.[1]
ITC analysis of the escape mutant RSV F proteins (L141W and D489Y) showed a dramatic reduction in binding affinity for JNJ-53718678, preventing accurate determination of KD values.[1] |
| Cell Assay |
Using a cellular infectious assay in 96-well plates where Vero/TMPRSS2 cells are infected with recombinant hMPV65, the antiviral activity of JNJ-678 (JNJ-53718678) against hMPV is assessed. After treating cells with varying concentrations of JNJ-678 (JNJ-53718678), recombinant hMPV (1×104 PFU per well) is added. Viral replication is measured using fluorescence three days after virus exposure, and the EC50 is computed[1].
Antiviral activity against recombinant RSV and escape mutants was determined using a phenotypic cell-based infection assay with fluorescence read-out. HeLa cells were seeded in 384-well plates, treated with compound dilutions, and infected with RSV. Viral replication was quantified by measuring eGFP expression three days post-infection. Cytotoxicity (CC50) was determined in parallel by measuring cellular ATP content.[1] A real-time virus propagation assay was performed in A549 cells infected with wild-type or mutant RSV. Cells were stained with live-cell dyes and imaged every 60 hours. The percentage of infected (GFP-positive) cells was quantified over time to assess inhibition by JNJ-53718678.[1] The effect of JNJ-53718678 on the stability of prefusion RSV F was tested in a heat-shock flow cytometry assay. HEK293T cells expressing wild-type RSV F were heat-shocked at 55°C for 10 minutes in the presence of compound, and the remaining prefusion F was detected with conformation-specific antibodies.[1] Differential scanning fluorimetry (DSF) was used to measure the melting temperature (Tm) of soluble prefusion RSV F ectodomain in the presence of JNJ-53718678. The protein was mixed with compound and SYPRO Orange dye, and Tm was determined as the temperature at the lowest value of the first derivative of the fluorescence signal.[1] |
| Animal Protocol |
Rats [1]
At 24, 48, and 72 hours following viral infection, cotton rats are given either a single dose or once-daily doses of 40 mg/kg JNJ-678 (JNJ-53718678) by oral gavage. In every experiment, the reduction in viral replication is contrasted with challenged animals that were given only the vehicle[1]. For cotton rat efficacy studies, animals were infected intranasally with RSV. JNJ-53718678 was administered orally (formulated in PEG400 + 1.1 eq HCl) either as a single prophylactic dose (1-100 mg/kg) 1 hour before infection, or as therapeutic doses (40 mg/kg) starting 24 hours post-infection (single or once-daily for 3 days). Viral titers in lung tissue and BALF were assessed 4 days post-infection by plaque assay and qRT-PCR.[1] For neonatal lamb studies, 1-3 day old lambs were infected with RSV via nebulization. JNJ-53718678 or JNJ-49214698 was formulated in 20% hydroxypropyl-β-cyclodextrin (acidified, pH ~2) and administered orally once daily at doses of 1, 5, or 25 mg/kg, starting 1 or 3 days post-infection for 5 or 3 consecutive days, respectively. Viral load and lung pathology were assessed on day 6 post-infection.[1] For mouse studies, BALB/c mice were infected intranasally with RSV. A single oral dose of 40 mg/kg JNJ-53718678 was administered 1 hour before infection. Lung viral titer, cytokine levels, and immune cell influx were analyzed on day 6.[1] Dog pharmacokinetic studies: JNJ-53718678 and JNJ-49214698 were formulated in 20% HP-β-CD solution (acidified). Beagle dogs received intravenous (1 mg/kg) or oral (5 mg/kg) doses in a crossover design. Blood samples were collected at multiple time points for plasma concentration analysis.[1] |
| ADME/Pharmacokinetics |
In canine pharmacokinetic studies, JNJ-53718678 showed favorable pharmacokinetic characteristics, supporting once-daily oral administration. [1]
JNJ-53718678 had a lung/plasma exposure ratio of 3.0, indicating good lung distribution. In contrast, a azabenzimidazole analog (compound F) had a lung/plasma exposure ratio of 0.4. [1] JNJ-49214698 had similar oral pharmacokinetic characteristics to JNJ-53718678. [1] |
| Toxicity/Toxicokinetics |
In HeLa cells, the average concentration (CC50) that achieves 50% cytotoxicity is very high, resulting in a selectivity index (SI) of JNJ-53718678 >10^5. [1]
|
| References | |
| Additional Infomation |
Rilematovir is being investigated in the clinical trial NCT04056611 (JNJ-53718678: Effects on adult and adolescent patients who have received hematopoietic stem cell transplantation and are infected with respiratory syncytial virus (RSV). Rilematovir is an orally administered inhibitor of the human respiratory syncytial virus (RSV) fusion protein (F protein) with potential antiviral activity. After oral administration, rilematovir specifically targets and binds to the F protein on the viral surface, thereby inhibiting RSV F protein-mediated fusion of the virus with the host cell membrane and preventing viral entry into the cell. This can block RSV replication, reduce viral load, and alleviate disease severity. The RSV F protein is a viral surface glycoprotein that plays a crucial role in the fusion of RSV with target cells and its entry into target cells.
JNJ-53718678 is a small molecule RSV fusion inhibitor that binds to and stabilizes the pre-fusion conformation of the RSV F protein, preventing it from folding into the necessary post-fusion state. [1] This compound is currently undergoing clinical evaluation for the treatment of RSV infection in hospitalized infants. [1] Structural analysis shows that JNJ-53718678 binds asymmetrically to the triple symmetric cavity of the pre-fusion RSV F protein and forms a key aromatic stacking interaction with Phe140 and Phe488 residues. [1] The therapeutic window for RSV antiviral drugs may be wider than previously thought, as delayed treatment up to 3 days after infection still showed significant efficacy in lambs. [1] |
| Molecular Formula |
C21H20CLF3N4O3S
|
|---|---|
| Molecular Weight |
500.92
|
| Exact Mass |
500.089
|
| Elemental Analysis |
C, 50.35; H, 4.02; Cl, 7.08; F, 11.38; N, 11.18; O, 9.58; S, 6.40
|
| CAS # |
1383450-81-4
|
| PubChem CID |
118892432
|
| Appearance |
White to off-white solid powder
|
| Density |
1.5±0.1 g/cm3
|
| Boiling Point |
672.5±55.0 °C at 760 mmHg
|
| Flash Point |
360.5±31.5 °C
|
| Vapour Pressure |
0.0±2.1 mmHg at 25°C
|
| Index of Refraction |
1.634
|
| LogP |
3.19
|
| Hydrogen Bond Donor Count |
0
|
| Hydrogen Bond Acceptor Count |
7
|
| Rotatable Bond Count |
7
|
| Heavy Atom Count |
33
|
| Complexity |
825
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
ClC1C=CC2=C(C=1)C=C(CN1C(N(CC(F)(F)F)C3C=CN=CC1=3)=O)N2CCCS(C)(=O)=O
|
| InChi Key |
GTQTUABHRCWVLL-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C21H20ClF3N4O3S/c1-33(31,32)8-2-7-27-16(10-14-9-15(22)3-4-17(14)27)12-28-19-11-26-6-5-18(19)29(20(28)30)13-21(23,24)25/h3-6,9-11H,2,7-8,12-13H2,1H3
|
| Chemical Name |
3-((5-chloro-1-(3-(methylsulfonyl)propyl)-1H-indol-2-yl)methyl)-1-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one
|
| Synonyms |
JNJ-678; JNJ-53718678; JNJ 678; JNJ53718678; JNJ678; JNJ 53718678
|
| HS Tariff Code |
2934.99.03.00
|
| 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)
|
| Solubility (In Vitro) |
DMSO : 16~65 mg/mL ( 31.94~129.76 mM)
|
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.17 mg/mL (4.33 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 21.7 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: 2.17 mg/mL (4.33 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 21.7 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: ≥ 2.17 mg/mL (4.33 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: ≥ 2.17 mg/mL (4.33 mM) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9963 mL | 9.9816 mL | 19.9633 mL | |
| 5 mM | 0.3993 mL | 1.9963 mL | 3.9927 mL | |
| 10 mM | 0.1996 mL | 0.9982 mL | 1.9963 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.
 JNJ-53718678 binds to a threefold-symmetric cavity in prefusion RSV F.
Administration of RSV fusion inhibitors reduces infection in animal models.Nat Commun.2017 Aug 1;8(1):167. |
|---|
 NJ-53718678 inhibits RSV in different cellular infection models.aConcentration-inhibition response curves of JNJ-53718678 obtained from an infection of HeLa cells (green circlesandline) or HBECs (purple circlesandline) with RSV.Nat Commun.2017 Aug 1;8(1):167. |
 Effect of RSV fusion inhibitors on RSV-induced lung pathology in neonatal lambs.
Superposition of JNJ-53718678, BMS433771, and JNJ-49153390 binding modes.Nat Commun.2017 Aug 1;8(1):167. |
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
COA
