EVT-401
EVT-401 is an orally active, potent and highly selective human P2X7R antagonist, with an IC50 of 10 nM and a Ki of 7.6 nM for human P2X7R, and an IC50 of 220 nM for mouse P2X7R. EVT-401 promotes apoptosis and induces cell cycle arrest in human rheumatoid arthritis synovial fibroblasts (RA SF), reduces the production of proinflammatory and joint-destructive mediators, and mitigates aggressive phenotypes. EVT-401 exhibits favorable oral bioavailability and a good safety profile, making it suitable for research into rheumatoid arthritis.
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- No. CAS: 951015-69-3
- Fòrmula: C22H20F4N2O3
- Peso molecular:436.40
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Almacenamiento:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Descripciòn
IC50 & Target
[1]|
hP2X7R 10 nM (IC50) |
hP2X7R 7.6 nM (Ki) |
rP2X7R 220 nM (IC50) |
In Vitro
EVT-401 binds to hP2X7R with a Ki of 7.6 nM in radioligand binding assays, and Schild analysis yields a KB of 12.1 nM[1].
EVT-401 inhibits hP2X7R-mediated calcium influx with an IC50 of 10 nM in calcium flux assays using 1321N1 cells, whereas its IC50 for rat P2X7R is 220 nM, and it shows no significant inhibition of P2X1/2/3/4 family members[1].
EVT-401 (10-200 μM; 24-96 h) exhibits low cytotoxicity in RA SF [1].
EVT-401 (50-200 μM; 24 or 48 h) promotes apoptosis in RA SF as determined by Annexin V/7-AAD flow cytometry[1].
EVT-401 (100 μM; 24 h) induces G0/G1 cell cycle arrest in RA SF and reduces the levels of G0/G1-related proteins including Cdk2, Rb and p-Rb[1].
EVT-401 (100 μM; 24 h) significantly reduces IL-6 secretion and downregulates MMP-3 and DKK-1 expression in a TNF-α-induced RA SF inflammatory model[1].
EVT-401 (10 or 100 μM; 24 h) inhibits the migration and invasion of RA SF in Transwell and wound healing assays[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:RA SF
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Concentration:10, 50, 100 and 200 μM
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Incubation Time:24, 48, 72 and 96 h
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Result:Showed low cytotoxicity in RA SF.
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Cell Line:RA SF
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Concentration:10, 50, 100 and 200 μM
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Incubation Time:24, 48, 72 and 96 h
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Result:At 100 μM partially inhibited RA SF proliferation after 72 h, while concentrations below 100 μM showed no obvious antiproliferative effects within 24, 48 or 72 h.
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Cell Line:RA SF
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Concentration:50, 100 and 200 μM
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Incubation Time:24 or 48 h
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Result:Promoted apoptosis in RA SF, as detected by Annexin V/7-AAD flow cytometry. The pro-apoptotic effect was more obvious.
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Cell Line:RA SF
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Concentration:50, 100 and 200 μM
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Incubation Time:24 h
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Result:Induced G0/G1 cell cycle arrest in RA SF.
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Cell Line:TNF-α-stimulated RA SF
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Concentration:10 and 100 μM
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Incubation Time:24 h
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Result:Suppressed TNF-α-induced transwell migration of RA SF.
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Cell Line:TNF-α-stimulated RA SF
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Concentration:10 and 100 μM
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Incubation Time:24 h
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Result:Inhibited the invasive potential of RA SF through Matrigel-coated transwell membranes.
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Cell Line:RA SF
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Concentration:10 and 100 μM
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Incubation Time:24 h
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Result:Reduced the levels of G0/G1 phase-related proteins, including Cdk2, Rb and p-Rb, in RA SF.
Parmacokinetics
| Species | Dose | Route | AUC0-t | MRT0-t | T1/2 | Tmax | CLz/F | Vz/F | Cmax |
|---|---|---|---|---|---|---|---|---|---|
| Cynomolgus Monkey[1] | 10 mg/kg | p.o. | 5407.69 μg/L·h | 11.65 h | 10.56 h | 3 h | 1.76 L/h/kg | 26.39 L/kg | 403.51 μg/L |
| Cynomolgus Monkey[1] | 100 mg/kg | p.o. | 34246.4 μg/L·h | 12.61 h | 9.87 h | 5.67 h | 3.15 L/h/kg | 45.94 L/kg | 2457.04 μg/L |
| Cynomolgus Monkey[1] | 30 mg/kg | p.o. | 11940.18 μg/L·h | 13.49 h | 12.86 h | 2.29 h | 2.46 L/h/kg | 42.66 L/kg | 891.24 μg/L |
In Vivo
EVT-401 (100 mg/kg; p.o.; once daily; for 8 weeks) significantly reduces clinical arthritis scores, shows a decreasing trend in serum CRP levels, and does not cause obvious pathological damage in the heart, liver, spleen, lung or kidney as assessed by H&E staining in cynomolgus monkey collagen-induced arthritis models[1].
EVT-401 (100 μM; s.c.; twice weekly; for 21 days) significantly inhibits RA SF invasion into cartilage in RA SF-cartilage co-transplantation NOD-SCID mouse models[1].
EVT-401 shows dose-dependent oral bioavailability of 42.2%, 30.9% and 26.6% at doses of 10, 30 and 100 mg/kg, respectively, in cynomolgus monkeys[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:Female Lewis rats with collagen-induced arthritis[1]
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Dosage:0.5, 5, and 50 mg/kg
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Administration:Oral gavage (p.o.); once daily; for 28 days
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Result:Showed detectable differences in plasma concentrations.
Did not exhibit significant therapeutic effects in this arthritis model.
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Animal Model:Cynomolgus monkeys with collagen-induced arthritis[1]
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Dosage:100 mg/kg
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Administration:Oral gavage (p.o.); once daily; for 8 weeks
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Result:Significantly reduced clinical arthritis scores. Showed a decreasing trend in serum CRP levels.
Did not cause obvious pathological damage in heart, liver, spleen, lung, or kidney by H&E staining.
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Animal Model:NOD-SCID mice with RA SF-cartilage co-transplantation[1]
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Dosage:100 μM
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Administration:Subcutaneous injection (s.c.); twice weekly; for 21 days
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Result:Significantly inhibited RA SF invasion into cartilage.
Chemical Information
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No. CAS 951015-69-3
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Peso molecular 436.40
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Fòrmula C22H20F4N2O3
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SMILES
FC(C=C1CC(NC2=C3C(C(N(C=C3)[C@H](C)CO)=O)=CC=C2C)=O)=C(C=C1)C(F)(F)F
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Envío
Room temperature in continental US; may vary elsewhere.
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Almacenamiento
Please store the product under the recommended conditions in the Certificate of Analysis.
Pureza y Documentación
Referencias
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
EVT-401 Related Classifications
HY-178230 Related Classifications
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