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| 25mg |
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Purity: ≥98%
PF429242 dihydrochloride is a novel, potent, reversible and competitive S1P [sterol regulatory element-binding protein (SREBP) site 1 protease] inhibitor with an IC50 of 170 nM. PF 429242 showed no significant inhibition of trypsin, elastase, proteinase K, plasmin, kallikren, factor XIa, thrombin, or furin at concentrations up to 100 μM and only modest inhibition of urokinase (IC50 = 50 μM) and factor Xa (IC50 = 100 μM). PF-429242 is selective for site 1 protease against a panel of serine proteases. PF-429242 inhibits rate of cholesterol synthesis in CHO cells with IC50 of 0.53 μM.
| Targets |
In Chinese hamster ovary cells, 10 μM PF-429242 disrupts the natural processing of SREBP. As well as downregulating endogenous SREBP target gene expression in cultured HepG2 cells, PF-429242 also inhibited the signal of the SRE luciferase reporter gene in human embryonic kidney 293 cells. With an inhibitory concentration of 0.5 μM, PF-429242 suppresses the synthesis of cholesterol in HepG2 cells [1]. Viral RNA copies and infectious virus titers were dramatically reduced in cell culture fluids upon the addition of PF-429242 (30 μM). In human HEK-293, Hep G2, and non-human primate LLC-MK2 cell cultures, PF-429242 treatment also decreased the formation of DENV2 [2]. This chemical, PF-429242, has strong antiviral action against both LCMV and LASV in cultured cells. It also effectively prevents GPC processing by prototypic arenaviruses, such as lymphocytic choriomeningitis virus (LCMV) and LASV [3].
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| ln Vitro |
In Chinese hamster ovary cells, 10 μM PF-429242 disrupts the natural processing of SREBP. As well as downregulating endogenous SREBP target gene expression in cultured HepG2 cells, PF-429242 also inhibited the signal of the SRE luciferase reporter gene in human embryonic kidney 293 cells. With an inhibitory concentration of 0.5 μM, PF-429242 suppresses the synthesis of cholesterol in HepG2 cells [1]. Viral RNA copies and infectious virus titers were dramatically reduced in cell culture fluids upon the addition of PF-429242 (30 μM). In human HEK-293, Hep G2, and non-human primate LLC-MK2 cell cultures, PF-429242 treatment also decreased the formation of DENV2 [2]. This chemical, PF-429242, has strong antiviral action against both LCMV and LASV in cultured cells. It also effectively prevents GPC processing by prototypic arenaviruses, such as lymphocytic choriomeningitis virus (LCMV) and LASV [3].
PF-429242 suppresses dengue virus (DENV) propagation in multiple primate-derived cell lines (HeLa, HEK-293, Hep G2, LLC-MK2). The 50% inhibitory concentration (IC₅₀) against DENV2 (strain 16681) in HeLa cells is 6.7 µM (95% CI: 4.0–11.2 µM), and the 90% inhibitory concentration (IC₉₀) is 35.5 µM (95% CI: 12.0–106.2 µM). The compound exhibits antiviral activity against all four DENV serotypes (DENV1–4). Drug-resistant DENV mutants did not emerge after five sequential passages under PF-429242 treatment. The reduction of intracellular cholesterol and lipid droplets induced by PF-429242 was not reversed by exogenous cholesterol or fatty acid supplementation, indicating that lipid depletion is not the primary mechanism of antiviral action.[2] |
| ln Vivo |
The expression of hepatic SREBP target genes was suppressed and the rates of hepatic fatty acid and cholesterol synthesis were decreased in mice given PF-429242 treatment for a full day [1].
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| Enzyme Assay |
Soluble S1P (ss1P) from conditioned medium of stably expressing HEK293 cells was used without further purification. For each reaction, 20 µL of conditioned medium containing ss1P was pre-incubated with indicated concentrations of PF-429242 for 20 minutes at room temperature. The fluorogenic peptide substrate Succ-YISRRLL-MCA (20 µM final concentration) was then added. The reaction was performed in a buffer containing 25 mM Tris-HCl, 25 mM MES (pH 7.5), and 1 mM CaCl₂ in a total volume of 100 µL. Enzymatic activity was measured by detecting the liberated 7-amino-4-methylcoumarin (AMC) fluorophore using a fluorescence plate reader with excitation at 360 nm and emission at 460 nm.[3]
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| Cell Assay |
HeLa, HEK-293, Hep G2, and LLC-MK2 cells were seeded in plates and infected with DENV at a multiplicity of infection (MOI) of 0.001–1 in medium containing PF-429242 or DMSO control. Viral titers in culture fluids were quantified by focus-forming assay (FFA) and real-time RT-PCR at 24, 48, and 72 hours post-infection. Cytotoxicity was assessed by measuring intracellular ATP levels after 72 hours of drug treatment using a luminescence-based assay. Intracellular cholesterol was quantified using a cholesterol assay kit, and lipid droplets were stained with BODIPY 493/503 and measured by fluorescence. For rescue experiments, cholesterol lipid concentrate (500 µg/mL) or sodium oleate (20 µM) was added concurrently with PF-429242 to restore lipid levels. Localization of viral proteins and lipid droplets was analyzed by immunofluorescence and confocal microscopy.[2]
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| Toxicity/Toxicokinetics |
In HeLa cells, the 50% cytotoxic concentration (CC₅₀) of PF-429242 was 236.7 µM (95% CI: 87.6–639.2 µM) after 72 hours of treatment. No significant morphological changes were observed in cells treated with the antiviral concentration. [2]
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| References |
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| Additional Infomation |
PF-429242 is a lipid-lowering drug that reduces cellular lipid levels by inhibiting S1P to block the processing of SREBP. It has been previously reported that PF-429242 can inhibit the replication of hepatitis C virus, Lassa virus, lymphocytic choriomeningovirus and New World Arena virus. In dengue virus infection, its antiviral effect occurs in the later stages of infection (48-72 hours after infection), suggesting that it may affect host cytokines rather than directly target the processing of viral polyproteins. This compound is considered a promising candidate for dengue fever treatment, but its exact mechanism of action against dengue virus is unclear. [2]
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| Molecular Formula |
C25H37CL2N3O2
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|---|---|
| Molecular Weight |
482.486184835434
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| Exact Mass |
481.226
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| CAS # |
2248666-66-0
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| Related CAS # |
PF-429242;947303-87-9
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| PubChem CID |
90488837
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| Appearance |
White to light brown solid powder
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
10
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| Heavy Atom Count |
32
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| Complexity |
503
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CCN(CC)CC1=CC=C(C=C1)C(=O)N(CCC2=CC=CC=C2OC)[C@@H]3CCNC3.Cl.Cl
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| InChi Key |
GSUZWFZKTIOWTI-MQWQBNKOSA-N
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| InChi Code |
InChI=1S/C25H35N3O2.2ClH/c1-4-27(5-2)19-20-10-12-22(13-11-20)25(29)28(23-14-16-26-18-23)17-15-21-8-6-7-9-24(21)30-3;;/h6-13,23,26H,4-5,14-19H2,1-3H3;2*1H/t23-;;/m1../s1
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| Chemical Name |
4-(diethylaminomethyl)-N-[2-(2-methoxyphenyl)ethyl]-N-[(3R)-pyrrolidin-3-yl]benzamide;dihydrochloride
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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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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 : ≥ 83.3 mg/mL (~172.65 mM)
H2O : ~50 mg/mL (~103.63 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.18 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 (5.18 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 (5.18 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: 100 mg/mL (207.26 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0726 mL | 10.3629 mL | 20.7258 mL | |
| 5 mM | 0.4145 mL | 2.0726 mL | 4.1452 mL | |
| 10 mM | 0.2073 mL | 1.0363 mL | 2.0726 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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