| Size | Price | |
|---|---|---|
| 500mg | ||
| 1g | ||
| Other Sizes |
| Targets |
NLRP3; DFV890 is a new, orally administered, potent, and selective low-molecular-weight compound designed to inhibit the activity of the NLRP3 inflammasome. It functions by directly binding to NLRP3 and locking the protein in an inactive conformation, thus preventing NLRP3 inflammasome assembly in response to sterile danger signals. [1]
|
|---|---|
| ln Vitro |
DFV890 blocks the activation of NLRP3, which leads to the inhibition of the maturation of the pro-inflammatory cytokines IL-1β and IL-18, along with the prevention of pyroptotic cell death. [1]
In mechanistic mouse models, DFV890 was shown to inhibit IL-1β and IL-18 secretions and pyroptotic cell death. [1] |
| ln Vivo |
This study is a Phase 2a randomized clinical trial evaluating DFV890 in patients with COVID-19 pneumonia and impaired respiratory function. [1]
Efficacy on APACHE II Score: The primary endpoint, which was to establish clinical efficacy based on the combined APACHE II score at Day 14 or day-of-discharge (whichever came first) with worst-case imputation for death, was not met. The adjusted least-squares mean (LSM [SE]) for the combined APACHE II score for DFV890 + SoC vs. SoC alone was 8.7 (1.06) vs. 8.6 (1.05) (LSM difference with 90% CI, 0.11 [-2.0, 2.3]; p = 0.467). [1] Efficacy on Clinical Status: A higher percentage of patients treated with DFV890 showed at least a one-level improvement in clinical status on the WHO 9-point ordinal scale compared to SoC alone at Day 14 (84.3% vs. 73.6%) and Day 28 (87.1% vs. 83.3%). [1] Efficacy on Viral Clearance: Patients receiving DFV890 cleared SARS-CoV-2 earlier. At Day 7, a higher proportion of participants receiving DFV890 (76.4%) achieved SARS-CoV-2 clearance vs. SoC (57.4%). By Day 14, the proportion testing positive was comparable between groups (23.6% vs. 22.4%). [1] Efficacy on Survival and Ventilation: Mechanical ventilation-free survival through Day 28 was 85.7% in the DFV890 group vs. 80.6% in the SoC group. The incidence of fatal events was lower in the DFV890 group through Day 28 (8.6% vs. 11.1%). [1] Efficacy on Inflammatory Markers: Mean CRP levels decreased over time in both groups. Lower mean CRP values were observed in the DFV890 group during Week 1, with no notable difference thereafter (p = 0.237). IL-6 levels were lower in the DFV890 group on Day 3. [1] Post-hoc Analysis: In a post-hoc analysis of patients with more severe inflammation (baseline CRP > 78.8 mg/L) who received low-dose corticosteroids (≤10 mg daily average in the first week), DFV890 treatment showed an earlier reduction and lower levels of CRP, IL-6, and IP-10, as well as lower mean APACHE II scores and earlier reduction in body temperature over 2 weeks compared to SoC. [1] |
| Enzyme Assay |
This clinical study did not perform direct enzyme assays. The mechanism of action is described based on preclinical data: DFV890 inhibits NLRP3 activity by directly binding to the NLRP3 protein and locking it in an inactive conformation, thereby preventing inflammasome assembly. [1]
|
| Cell Assay |
This clinical study did not perform new cell-based assays. It references preclinical data showing that DFV890 inhibits IL-1β and IL-18 secretions and pyroptotic cell death in vitro and in mechanistic mouse models. [1]
|
| Animal Protocol |
This randomised, multinational study enrolled hospitalised patients (18-80 years) with COVID-19-associated pneumonia and impaired respiratory function. Eligible patients were randomised (1:1) via Interactive Response Technology to DFV890 + standard-of-care (SoC) or SoC alone for 14 days. Primary endpoint was APACHE II score at Day 14 or on day-of-discharge (whichever-came-first) with worst-case imputation for death. Other key assessments included clinical status, CRP levels, SARS-CoV-2 detection, other inflammatory markers, in-hospital outcomes, and safety. [1]
|
| ADME/Pharmacokinetics |
Dosing Regimen in Humans: DFV890 was administered orally at a dose of 50 mg twice daily (b.i.d.), approximately 12 hours apart (morning and evening), for 14 days (28 doses). [1]
Administration in Intubated Patients: If a patient became intubated and was unable to ingest tablets, the study drug was administered through a nasogastric tube (8 French or greater). [1] Steady-State Concentration: Patients receiving DFV890 50 mg b.i.d. rapidly achieved stable steady-state plasma concentrations, as illustrated by relatively stable troughs over time after 72 hours of treatment, with no further accumulation during the 2-week treatment period. [1] Trough Concentrations: The mean trough concentrations on Days 1, 3, and at the end of treatment (Day 14) were 1340 ng/mL, 1550 ng/mL, and 1690 ng/mL, respectively, with a coefficient of variation between 64.2% and 67.7%. [1] |
| Toxicity/Toxicokinetics |
General Safety: DFV890 was generally well tolerated with no unexpected safety signals identified in the COVID-19 population. [1]
Adverse Events (AEs): The proportion of patients with any AE was 58.6% in the DFV890 group and 54.2% in the SoC group. Most AEs were of mild intensity (40.1% overall). [1] Serious Adverse Events (SAEs): SAEs were reported in 22.9% of patients in the DFV890 group and 15.3% in the SoC group. No drug-related SAEs were reported in either treatment arm. [1] Study Drug-Related AEs: Study drug-related AEs were reported in 21.4% of patients in the DFV890 group. None were reported in the SoC group. [1] Fatal Events: Fatal events leading to death up to Day 28 occurred in 8.6% of patients in the DFV890 group and 11.1% in the SoC group. [1] Specific AEs: DFV890 was associated with a higher number of maculopapular/pruritic skin rashes of mild and moderate intensity. The most frequent AEs in the DFV890 group by system organ class included gastrointestinal disorders (17.1%), metabolism and nutrition disorders (15.7%), and skin and subcutaneous tissue disorders (15.7%). [1] Discontinuations: AEs leading to discontinuation occurred in 8 (11.4%) patients in the DFV890 group. No discontinuations due to AEs were reported in the SoC group. None of these were considered study drug-related. [1] |
| References |
|
| Additional Infomation |
Background/Rationale: DFV890 is a new, potent, and selective low-molecular-weight inhibitor of NLRP3. It is being tested for the first time in this proof-of-mechanism study in patients with severe COVID-19 pulmonary disease. By inhibiting NLRP3, it blocks IL-1β and IL-18 secretion and pyroptotic cell death, suggesting its potential use in mitigating the cytokine storm and resultant coronavirus-associated acute respiratory distress syndrome (CARDS) in COVID-19. [1]
Study Design Summary: This was a Phase 2, randomized, controlled, open-label, multicenter study. Hospitalized patients (18-80 years) with COVID-19 pneumonia and impaired respiratory function were randomized 1:1 to receive DFV890 (50 mg orally b.i.d. for 14 days) plus standard-of-care (SoC) or SoC alone. [1] Key Inclusion Criteria: Patients were required to have a confirmed SARS-CoV-2 infection, COVID-19-associated pneumonia (evidenced by imaging), impaired respiratory function (SpO2 ≤ 93% on room air or PaO2/FiO2 < 300 mmHg), APACHE II score ≥ 10, and CRP ≥ 20 mg/L and/or ferritin ≥ 600 μg/L at screening. [1] Interpretation of Primary Outcome: Although the primary endpoint (APACHE II score) was not met, the observed improvements in clinical status, faster viral clearance, and numerically better survival outcomes suggest that DFV890 may offer benefits during the NLRP3 activation phase of the disease. The therapeutic effect may have been masked in the overall population by the broad anti-inflammatory effect of high-dose corticosteroids, as suggested by a post-hoc analysis. [1] Potential Broader Application: Since DFV890 interferes with the host inflammatory response (cytokine storm) rather than targeting viral particles directly, it may be expected to work independently of underlying SARS-CoV-2 variants. [1] Future Research: The role of DFV890 in preventing or treating CARDS, as well as its potential in other NLRP3-related inflammatory conditions such as cryopyrin-associated periodic syndromes (CAPS) and osteoarthritis, warrants further research. [1] |
| Molecular Formula |
C19H24N4O3S2
|
|---|---|
| Molecular Weight |
420.548861503601
|
| Exact Mass |
420.128
|
| Elemental Analysis |
C, 54.26; H, 5.75; N, 13.32; O, 11.41; S, 15.25
|
| CAS # |
2271394-34-2
|
| PubChem CID |
156440583
|
| Appearance |
White to off-white solid powder
|
| Density |
1.55±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)
|
| LogP |
4.7
|
| Hydrogen Bond Donor Count |
4
|
| Hydrogen Bond Acceptor Count |
6
|
| Rotatable Bond Count |
4
|
| Heavy Atom Count |
28
|
| Complexity |
704
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
S(C1=CN=C(C(C)(C)O)S1)(=N)(NC(NC1=C2CCCC2=CC2CCCC=21)=O)=O
|
| InChi Key |
LHVWNNYPUDZLSH-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C19H24N4O3S2/c1-19(2,25)17-21-10-15(27-17)28(20,26)23-18(24)22-16-13-7-3-5-11(13)9-12-6-4-8-14(12)16/h9-10,25H,3-8H2,1-2H3,(H3,20,22,23,24,26)
|
| Chemical Name |
1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[[2-(2-hydroxypropan-2-yl)-1,3-thiazol-5-yl]sulfonimidoyl]urea
|
| Synonyms |
NLRP3 antagonist 2; 2271394-34-2; NVP-DFV890; (R)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide; DFV890; DFV 890; NVP-DFV-890; NVPDFV890; NVP DFV-890; orb2565669;
|
| HS Tariff Code |
2934.99.9001
|
| 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) |
Typically soluble in DMSO: ~100 mg/mL (237.8 mM)
|
|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3778 mL | 11.8892 mL | 23.7784 mL | |
| 5 mM | 0.4756 mL | 2.3778 mL | 4.7557 mL | |
| 10 mM | 0.2378 mL | 1.1889 mL | 2.3778 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.
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
