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| Targets |
ERDRP-0519 targets the RNA-dependent RNA polymerase (RdRp) complex of morbilliviruses, specifically the large (L) protein subunit. It binds within a conserved pocket in the RdRp palm domain, adjacent to the GDNQ catalytic motif. [1][2][4]
For measles virus (MeV), the EC50 values against a panel of representative genotypes range from 0.07 to 0.3 μM. The EC50 for canine distemper virus (CDV) strain 5804PeH is approximately 0.14 μM, and for the neuroadapted Snyder Hill strain approximately 0.16 μM. [1] For Nipah virus (NiV, Malaysia strain), the EC50 in a mini-replicon assay is 1.6 μM (95% CI: 1.4–1.8 μM). The binding affinity (KD) of ERDRP-0519 for purified NiV polymerase is ~208 nM, while for peste des petits ruminants virus (PPRV) polymerase it is 3.6 nM. [4] |
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| ln Vitro |
ERDRP-0519 potently inhibits measles virus replication in cell culture. Against a panel of MeV isolates representing seven endemic genotypes (including B3, C2, D3, D6, D7, H), the EC50 values range from 0.07 to 0.3 μM, with selectivity indices (SI = CC50/EC50) >200. It also inhibits pathogenic CDV strains 5804PeH and Snyder Hill with EC50 values of approximately 0.14 μM and 0.16 μM, respectively. [1]
In a mini-replicon reporter assay, ERDRP-0519 blocks the activity of both MeV and CDV polymerase complexes with EC50 values around 0.12 μM, while it does not inhibit the respiratory syncytial virus (RSV) replicon even at 10 μM, demonstrating specificity for morbilliviruses. [1] In human peripheral blood mononuclear cells (PBMCs) infected with MeV, ex vivo recapitulation of PK-informed b.i.d. dosing (target steady-state concentration ~1.5 μM) reduced progeny virus titers by more than three orders of magnitude (>99.9% reduction) compared to untreated controls. [3] In vitro primer-dependent and de novo RNA synthesis assays using purified MeV and NiV polymerases show that ERDRP-0519 inhibits both modes of RNA synthesis, with greater potency against de novo initiation. For MeV, 1 μM substantially inhibits de novo synthesis; for NiV, 10 μM substantially inhibits de novo synthesis. [4] The compound shows low cytotoxicity in established human and animal cell lines and primary human PBMCs. The CC50 in Vero cells is >75 μM, and in BSR-T7/5 cells >100 μM. [1][4] ERDRP-0519 showed effectiveness with EC50 of 0.07-0.3 µM against a panel of measles virus (MeV) isolates[1]. MeV and Morbillivirus-related infections, including canine distemper virus (CDV), have been shown to be effectively inhibited by ERDRP-0519 [3]. |
| ln Vivo |
CDV/ferret model (lethal surrogate for human measles) : Oral administration of ERDRP-0519 at 50 mg/kg twice daily (b.i.d.) for 14 days showed significant efficacy. Prophylactic treatment (starting 24 h pre-infection) prolonged survival and reduced viremia (~250-fold reduction at peak) and lymphopenia. Post-exposure therapeutic (PET) treatment starting at the onset of viremia (day 3 post-infection) resulted in complete survival of all animals, ~99% reduction in viral load, and only mild transient lymphopenia. All PET-treated animals mounted strong neutralizing antibody responses and were fully protected against lethal re-challenge at day 35. [1]
Squirrel monkey model of measles: Squirrel monkeys were infected intranasally with a clinical MeV isolate (genotype D8). Prophylactic treatment (starting 12 h pre-infection) prevented any measles-like clinical signs (rash, fever). Therapeutic treatment starting at day 3 post-infection (onset of viremia) markedly reduced viremia (up to 250-fold at day 7) and prevented generalized rash. Therapeutic treatment starting at day 7 post-infection (onset of clinical signs) did not significantly reduce peak viremia but accelerated viral clearance in throat swabs (two orders of magnitude reduction within 72 h) and prevented generalized rash. All treated animals developed protective neutralizing antibody titers (≥120). [3] Squirrel monkeys were given a single dose of ERDRP-0519 (50 mg/kg) orally (intragastrically), and blood was drawn seven days later for pharmacokinetic (PK) analysis. The peak value of serum concentration (Cmax = 3.27 µM) is reached about two hours post-administration [3]. |
| Enzyme Assay |
In vitro primer-dependent and de novo RNA synthesis inhibition : Purified MeV or NiV L-P polymerase complex (1.8 μM) was pre-incubated with 10-fold serial dilutions of ERDRP-0519 (0.01–100 μM) or DMSO control for 30 min at room temperature. Reactions were initiated by adding a biotin-labeled RNA template (5'-AGUGUGUGGU-3') with or without a pACCA primer, along with 2 mM each of ATP and CTP, in buffer containing 6 mM MnCl2. After 1 h at 28°C, reactions were stopped, and products were resolved on 22% denaturing polyacrylamide/7 M urea gels, stained with Stains-All, and quantified. For MeV, 1 μM ERDRP-0519 substantially inhibited de novo synthesis; for NiV, 10 μM showed substantial inhibition. [4]
Microscale thermophoresis (MST) binding assay: Purified His-tagged polymerase complexes were fluorescently labeled with RED-tris-NTA dye. Compounds were serially diluted 1:1 in MST buffer (20 mM HEPES, 150 mM NaCl, 0.05% Tween-20, pH 7.5). Labeled protein (25–50 nM) was mixed with compound and incubated at room temperature. MST measurements were performed on a Monolith NT.115 instrument at 25°C. KD values were calculated using MO.Affinity Analysis software. ERDRP-0519 bound PPRV polymerase with a KD of 3.6 nM and NiV polymerase with a KD of ~208 nM. [4] Cryo-EM structure determination: Purified polymerase complexes were incubated with 10-fold molar excess of ERDRP-0519 and vitrified on holey grids. Cryo-EM data were collected on a Titan Krios at 300 kV, and structures were solved at resolutions of 2.66–2.73 Å. The compound was found bound in a pocket formed by RdRp motifs A–D. [4] |
| Cell Assay |
Mini-replicon luciferase reporter assay: BSR-T7/5 cells were transfected with plasmids encoding viral L, P, N proteins and a Gaussia luciferase (GLuc) reporter under a T7 promoter. Six hours post-transfection, cells were treated with three-fold serial dilutions of ERDRP-0519 (starting at 90 μM for NiV or 30 μM for MeV/PPRV) or DMSO control. At 48 h post-transfection, supernatants were collected and Renilla luciferase activity was measured. EC50 values were calculated by four-parameter logistic regression. [4]
Antiviral efficacy in Vero E6 cells: Cells were infected with authentic NiV (Bangladesh or Malaysia strain) at MOI 0.01 in the presence of two-fold serial dilutions of ERDRP-0519. After 1 h adsorption, unbound virus was washed, and medium with compound was added. Supernatants were collected at 24 h post-infection, and viral RNA copy numbers were quantified by RT-qPCR. [4] Cytotoxicity assay: Vero E6 or BSR-T7/5 cells were treated with serial dilutions of ERDRP-0519 or DMSO for 24–48 h. Viability was measured using WST-1 assay (absorbance at 450 nm) or CellTiter-Lumi™ II luminescent assay (ATP quantification). The CC50 in Vero cells was >75 μM. [1][4] |
| Animal Protocol |
CDV/ferret study: Male and female adult European ferrets (no immunity to CDV) were infected intranasally with 1×10⁵ TCID₅₀ of CDV-5804PeH. ERDRP-0519 was formulated in PEG-200/0.5% methylcellulose (10/90) and administered via gastric gavage at 50 mg/kg body weight twice daily (b.i.d.) for 14 days. Prophylactic dosing started 24 h pre-infection; therapeutic dosing started on day 3 post-infection (onset of viremia). Control animals received vehicle only. Blood samples were collected from the jugular vein on days 0, 3, 7, 10, 14, and weekly thereafter. [1]
Squirrel monkey study: Adult squirrel monkeys (Saimiri sciureus) were infected intranasally with 10⁶ TCID₅₀ of MeV isolate MV/FrankfurtMain.DEU/17.11 (genotype D8). ERDRP-0519 was formulated in PEG-200/0.5% methylcellulose and administered orally (intragastric) at 50 mg/kg b.i.d. for 14 days. Prophylactic treatment started 12 h pre-infection; therapeutic treatment started on day 3 or day 7 post-infection. Blood samples and throat swabs were collected twice weekly. Clinical signs (rash, fever), body weight, and white blood cell counts were monitored. [3] |
| ADME/Pharmacokinetics |
Rat: Single oral dose of ERDRP-0519 showed an oral bioavailability of 39%. [1]
Ferret: After a single oral dose of 50 mg/kg, peak plasma concentration (Cmax) exceeded 1,500 ng/mL (~3.5 μM), which is approximately 5-fold higher than the in vitro EC50 for CDV. Serum protein binding was <95%. The compound was shelf-stable at ambient temperature for >1 year. [1] Squirrel monkey: Single oral dose of 50 mg/kg resulted in a Cmax of 3.27 μM reached approximately 2 hours post-dose, with terminal elimination half-life (t½) not specified but consistent with b.i.d. dosing. Trough concentrations during multi-dose b.i.d. administration averaged ~1.6 μM, exceeding the 1.5 μM threshold needed for near-sterilizing ex vivo efficacy. No drug accumulation was observed with repeated dosing. [3] |
| Toxicity/Toxicokinetics |
In the CDV/ferret study, twice-daily oral administration of 50 mg/kg ERDRP-0519 for 14 days was well tolerated with no signs of adverse effects. In the squirrel monkey study, one animal in the day 3 therapeutic group developed mild diarrhea and died on day 15 post-infection. Histological analysis of the liver and gut showed no pathological alterations attributable to the compound; the death was concluded to be unrelated to ERDRP-0519 administration or MeV infection. No other treatment-related adverse events were observed. In vitro, the compound showed no significant cytotoxicity in Vero cells (CC50 >75 μM) or BSR-T7/5 cells (CC50 >100 μM). [1][3]
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| References | |
| Additional Infomation |
Mechanism of action: ERDRP-0519 is a non-nucleoside allosteric inhibitor of the morbillivavirus RdRp. Cryo-EM structures show it binds in a pocket formed by RdRp motifs A–D, sterically blocking template RNA and incoming nucleotide binding, thus inhibiting both initiation and elongation of RNA synthesis. Resistance mutations map to the L protein near the GDNQ catalytic motif (e.g., L589Y, L776A) and are associated with reduced viral fitness and attenuated pathogenicity. [1][4]
Cross-inhibition of other paramyxoviruses: ERDRP-0519 inhibits Nipah virus (NiV) with lower potency (EC50 ~1.6 μM). It does not inhibit polymerases of RSV, mumps virus, Newcastle disease virus, PIV3, or PIV5 at up to 100 μM. [4] Structure-guided optimization: Derivatives GL22 (with piperazine and tris-hydroxymethyl-imino-acetamide extensions) and G671 (with lipophilic benzonitrile) were designed based on cryo-EM structures. G671 showed improved potency against NiV (EC50 ~0.6 μM) and binding affinity (KD ~52 nM). [4] Resistance profile: In vitro adaptation of CDV and MeV in the presence of ERDRP-0519 yielded escape mutations (e.g., L589Y, L776A) that confer resistance but also reduce viral fitness and transmission, making sustained circulation of resistant variants unlikely. No resistance mutations were detected in viruses re-isolated from treated animals. [1][3] |
| Molecular Formula |
C23H30F3N5O4S
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|---|---|
| Molecular Weight |
529.575614452362
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| Exact Mass |
529.197
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| Elemental Analysis |
C, 52.16; H, 5.71; F, 10.76; N, 13.22; O, 12.08; S, 6.05
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| CAS # |
1374006-96-8
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| PubChem CID |
57521469
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| Appearance |
White to off-white solid powder
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| LogP |
2.4
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
36
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| Complexity |
842
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CN1C(=CC(=N1)C(F)(F)F)C(=O)NC2=CC=C(C=C2)S(=O)(=O)N3CCCC[C@H]3CCN4CCOCC4
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| InChi Key |
JVZHTUQIMBYDSX-SFHVURJKSA-N
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| InChi Code |
InChI=1S/C23H30F3N5O4S/c1-29-20(16-21(28-29)23(24,25)26)22(32)27-17-5-7-19(8-6-17)36(33,34)31-10-3-2-4-18(31)9-11-30-12-14-35-15-13-30/h5-8,16,18H,2-4,9-15H2,1H3,(H,27,32)/t18-/m0/s1
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| Chemical Name |
2-methyl-N-[4-[(2S)-2-(2-morpholin-4-ylethyl)piperidin-1-yl]sulfonylphenyl]-5-(trifluoromethyl)pyrazole-3-carboxamide
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| Synonyms |
ERDRP0519; ERDRP 0519; ERDRP-05,19; 1374006-96-8; 1-Methyl-N-[4-[[(2S)-2-[2-(4-morpholinyl)ethyl]-1-piperidinyl]sulfonyl]phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; V5S4Z5Q9VU; DTXSID101028018; ERDRP-0519
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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 : ~100 mg/mL (~188.83 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.72 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 (4.72 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 (4.72 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 | 1.8883 mL | 9.4414 mL | 18.8829 mL | |
| 5 mM | 0.3777 mL | 1.8883 mL | 3.7766 mL | |
| 10 mM | 0.1888 mL | 0.9441 mL | 1.8883 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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