NA808
NA808 is an Serine Palmitoyltransferase (SPT) inhibitor. NA808 reduces sphingomyelin synthesis, inhibits its activation in hepatic stellate cells, and decreases the expression of α-SMA protein and mRNA, as well as collagen 1A1 mRNA (IC50 0.16, 0.12, and 0.11 μM, respectively). NA808 inhibits HCV replication and reduces NS3 and RdRp protein expression in HCV replicon cells without significant cytotoxicity and exhibits almost no immunosuppressive effect at effective concentrations. NA808 demonstrates broad-spectrum antiviral activity in humanized chimeric liver mice infected with various HCV genotypes, and dose-dependently reduces serum and hepatic HCV RNA levels. NA808 can be used for research on non-alcoholic steatohepatitis and hepatitis C virus infection.
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- CAS No.: 827034-92-4
- Formule: C35H49NO10
- Masse moléculaire:643.76
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Stockage:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Activité biologique
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Chemical Information
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- Références
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Activité biologique
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Serine palmitoyltransferase (SPT) |
NA808 (12.3-1000 nM; 4 days) concentration-dependently inhibits de novo synthesis of Cer, Glc Cer, and SM in E14C12 cells, with sub-maximum inhibition for Cer and GlcCer at 37 nM and for SM at 111 nM[1].
NA808 (7 days) concentration-dependently reduces α-SMA protein levels (IC50 = 0.16 μM) as well as α-SMA and collagen 1A1 mRNA expression (IC50 = 0.12 and 0.11 μM, respectively) in E14C12 cells without cytotoxicity[1].
NA808 (1-100 μM; 1-4 h) shows substrate characteristics for OATP1B1 and MRP2 in OATP1B1-MRP2 double-transfected MDCK II cells (Papp ratios 24.2-70.2, decreasing with increasing concentration), shows Papp ratios of approximately 1.0 in OATP1B1-BCRP double-transfected cells, and shows Papp ratios of approximately 1.0-1.1 in OATP1B1 single-transfected cells (no active transport)[2].
NA808 (0-250 nM) inhibits HCV replication in HCV genotype 1b subgenomic replicon cells (FLR3-1) with an IC50 of 0.84 µmol/L, without apparent cytotoxicity[3][4].
NA808 (5-25 nM; 0.25-72 h) shows noncompetitive inhibition of SPT enzymatic activity in FLR3-1 cell lysates and replicon cells[3][4].
NA808 (0-100 nM) dose-dependently inhibits de novo sphingolipid synthesis in FLR3-1 cells[3][4].
NA808 (48-72 nM, i.e., 4-6 × IC50; 14 passages) does not induce resistance mutations in HCV genotype 1b replicon cells (R6 FLR-N), with IC50 values remaining stable during passaging: 18.9 nM for untreated, 14.3 nM for 4 × IC50 treatment, and 19.8 nM for 6 × IC50 treatment[3].
NA808 shows little to no inhibitory effect on human peripheral blood T-cell proliferation at concentrations that suppress HCV replication[4].
NA808 (0-250 nM; 96 h) reduces HCV NS3 protein and RdRp (NS5B) protein expression levels in FLR3-1 replicon cells[4].
NA808 (0-1 μM) decreases sphingomyelin levels in the detergent-resistant membrane (DRM) fraction required for HCV replication, disrupting the association between RdRp and SM, thereby inhibiting HCV replication[4].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:FLR3-1 replicon cells
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Concentration:25 nM
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Incubation Time:96 h
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Result:Reduced HCV NS3 protein expression levels.
NA808 (5-10 mg/kg; i.v.; once daily; for 14-21 days) dose-dependently reduces serum HCV RNA levels and hepatic HCV RNA and core protein levels in humanized liver chimeric mice infected with HCV genotype 1a or 2a, without apparent toxicity. NA808 at 5 mg/kg for 21 days reduces serum HCV RNA to below the detection limit in 2 out of 5 mice[4].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:Humanized liver chimeric mice generated by transplanting human primary hepatocytes into uPA/SCID mice (purchased from PhoenixBio), which were intravenously injected with 10⁴ or 10⁶ copies/mouse of HCV-positive sera of genotypes 1a (HCG9), 1b (HCR6), 2a (HCR24), 3a (HCV-TYMM), or 4a (HCVgenotype4a/KM). Treatment was started 12 weeks after HCV inoculation[3][4]
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Dosage:This compound (1.5, 3, 5 mg/kg); PEG-IFN (30 μg/kg); RO-9187 (1000 mg/kg); HCV-796 (100 mg/kg); Telaprevir (400 mg/kg)
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Administration:This compound (i.v.; once daily; for 14 days); PEG-IFN (s.c.; twice weekly; for 14 days); RO-9187 (p.o.; once daily; for 14 days); HCV-796 (p.o.; once daily; for 14 days); telaprevir (p.o.; once daily; for 14 or 28 days)
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Result:Monotherapy with this compound (5 mg/kg) significantly reduced serum HCV RNA levels by approximately 2-log in HCV genotype 1a- and 1b-infected mice, and by approximately 1-3 log across genotypes 1a, 1b, 2a, 3a and 4a. Hepatic HCV RNA levels were also reduced in a dose-dependent manner at the end of treatment.
This compound (5 mg/kg) in combination with PEG-IFN reduced serum HCV RNA by approximately 4-log within 10 days, and to below the detection limit by day 14, in genotype 1a-, 2a-, and 4a-infected mice, with significant reductions in hepatic HCV RNA levels.
This compound (5 mg/kg) in combination with RO-9187, HCV-796, or telaprevir showed synergistic antiviral effects in genotype 1a-infected mice, with serum HCV RNA reductions of approximately 2.6-log, 3.5-log, and 2.5-log, respectively, within 14 days.
After 28 days of combination treatment with this compound (5 mg/kg) and telaprevir, serum HCV RNA levels were reduced by 10⁴-fold (4-log) in genotype 1a- or 1b-infected mice.
Triple combination of this compound (5 mg/kg), telaprevir, and HCV-796 reduced serum HCV RNA by approximately 4.7-log within 14 days in genotype 1a-infected mice.
No significant changes in human serum albumin levels were observed during the treatment period, suggesting no overt toxicity.
Showed no significant effect on serum HBV DNA levels in HBV genotype C-infected humanized liver chimeric mice.
Chemical Information
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CAS No. 827034-92-4
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Masse moléculaire 643.76
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Formule C35H49NO10
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SMILES
OC(C[C@](C(O)=O)(O)[C@H](/C=C/CCCCCCC(CCCCCCC)=O)C(N[C@H](C(O)=O)CC1=CC=C(C=C1)OCC#CC)=O)=O
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Livraison
Room temperature in continental US; may vary elsewhere.
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Stockage
Please store the product under the recommended conditions in the Certificate of Analysis.
Pureté et documentation
Références
[1]. Hada N, et al. Novel oral SPT inhibitor CH5169356 inhibits hepatic stellate cell activation and ameliorates hepatic fibrosis in mouse models of non-alcoholic steatohepatitis (NASH). Pharmacol Res Perspect. 2023 Jun;11(3):e01094. [Content Brief]
[2]. Yamane M, et al. Evaluation of the non-linearity of NA808 in liver not reflected in plasma using a rat pharmacokinetic study and PBPK modelling. Xenobiotica. 2023 Dec;53(6-7):498-506. [Content Brief]
[3]. Katsume A, et al. A serine palmitoyltransferase inhibitor blocks hepatitis C virus replication in human hepatocytes. Gastroenterology. 2013 Oct;145(4):865-73. [Content Brief]
[4]. Hirata Y, et al. Self-enhancement of hepatitis C virus replication by promotion of specific sphingolipid biosynthesis. PLoS Pathog. 2012;8(8):e1002860. [Content Brief]
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
NA808 Related Classifications
HY-16342 Related Classifications
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- NA808
- 827034-92-4
- NA 808
- NA-808
- Aminotransferases (Transaminases)
- HCV
- E14C12 cells
- MDCK II cells
- FLR3-1 cells
- R6 FLR-N cells
- HuH-7 K4 cells
- JFH/K4 cells
- MH-14 cells
- hepatic stellate cell (HSC) activation
- sphingolipid de novo synthesis
- serine palmitoyltransferase (SPT) inhibition
- noncompetitive inhibition
- OATP1B1 and MRP2 substrate
- detergent-resistant membrane (DRM)
- HCV NS3 protein
- HCV RdRp (NS5B) protein
- drug resistance barrier
- immunosuppressive activity
- humanized liver chimeric mice
- HCV genotypes 1a
- 1b
- 2a
- 3a
- 4a
- HBV genotype C
- non-alcoholic steatohepatitis (NASH)
- hepatitis C virus (HCV) infection
- Inhibitor
- inhibitor
- inhibit