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Purity: ≥98%
PF429242 (PF-429242) 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 demonstrated only mild inhibition of urokinase (IC50 = 50 μM) and factor Xa (IC50 = 100 μM), and no significant inhibition of trypsin, elastase, proteinase K, plasmin, kallikren, factor XIa, thrombin, or furin at concentrations up to 100 μM. PF-429242 exhibits selectivity towards site 1 protease in contrast to a group of serine proteases. PF-429242 has an IC50 of 0.53 μM and inhibits the rate of cholesterol synthesis in CHO cells.
| Targets |
S1P ( IC50 = 170 nM )
PF-429242 suppresses the expression of important genes involved in the synthesis of fatty acids and cholesterol, stops the nuclear translocation of SREBP, and inhibits both pathways in cultured human liver (Hep-G2) cells without causing any cytotoxicity[1]. In various cells derived from primates, the addition of PF-429242 inhibits the viral propagation of all DENV serotypes[2]. |
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| ln Vitro |
PF-429242 suppresses the expression of important genes involved in the synthesis of fatty acids and cholesterol, stops the nuclear translocation of SREBP, and inhibits both pathways in cultured human liver (Hep-G2) cells without causing any cytotoxicity[1]. In various cells derived from primates, the addition of PF-429242 inhibits the viral propagation of all DENV serotypes[2].
PF-429242 prevented proteolytic processing and nuclear translocation of sterol regulatory element-binding protein (SREBP) in cultured human liver Hep-G2 cells, with complete inhibition observed at 10 µM. [1] The compound reduced the expression of key genes involved in cholesterol synthesis (e.g., HMG-CoA synthase; EC₅₀ = 0.3 µM) and fatty acid synthesis (e.g., fatty acid synthase; EC₅₀ = 2 µM) in Hep-G2 cells. [1] PF-429242 inhibited cholesterol synthesis (EC₅₀ = 600 nM) and fatty acid synthesis (43% inhibition at 10 µM) in Hep-G2 cells without causing cytotoxicity, as assessed by lactate dehydrogenase (LDH) release assay. [1] LDL receptor gene expression and LDL receptor-mediated LDL internalization were also inhibited by PF-429242, but to a lesser extent compared to its inhibition of cholesterol synthesis. LDL receptor-mediated LDL internalization was not altered at concentrations that produced 65% inhibition of cholesterol synthesis and was only inhibited by 35% at concentrations that inhibited cholesterol synthesis by >90%. [1] |
| ln Vivo |
PF-429242's PK data in rats indicate that it had a low oral bioavailability of 5% and a rapid clearance of 75 ml/min/kg[1].
In male CD1 mice, intraperitoneal administration of PF-429242 (10 and 30 mg/kg/dose every 6 hours for 24 hours) resulted in greater than 80% reductions in hepatic HMG-CoA synthase gene expression at both doses. [1] Dose-related reductions in fatty acid synthase gene expression (50% and 75% reduction at 10 and 30 mg/kg/dose, respectively) and inhibition of both cholesterol and fatty acid synthetic pathways (50% inhibition of both pathways at 10 mg/kg/dose; 80% inhibition for both pathways at 30 mg/kg/dose) were observed. [1] LDL receptor gene expression was not substantially altered at 10 mg/kg/dose but was reduced by 35% at 30 mg/kg/dose. [1] |
| Enzyme Assay |
The enzymatic activity and inhibition of S1P were measured fluorometrically using the MCA-conjugated peptidyl substrate Ac-VFRSLK-MCA. The reaction was conducted in a 96-well plate format with an assay volume of 40 µL. The fluorogenic peptide substrate concentration was 20 µM, and the purified His-tagged human S1P enzyme (secreted from stably transfected CHO-K1 cells and purified by nickel column affinity chromatography) concentration was 25 µg/mL (1 µg/well). The reaction proceeded for 4 hours at 37 °C. Test compounds dissolved in DMSO were added such that the final DMSO concentration in the assay was 2.5%. Fluorescence was measured with excitation at 360 nm and emission at 460 nm. [1]
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| Cell Assay |
HeLa cells are cultivated in medium enhanced with 2% FCS and 0.2 mM non-essential amino acids, containing 3 to 300 µM of PF-429242. The cultured cells are given a CellTiter-Glo mixture 72 hours after the medication is administered, and the intracellular ATP is measured for luminescence intensity using an ARVO MX/Light 1420 Multilabel/Luminescence counter.
Hep-G2 cells were cultured and treated with PF-429242. Proteolytic processing and nuclear translocation of SREBP were assessed. Gene expression of HMG-CoA synthase, fatty acid synthase, and LDL receptor was measured using established methods. Cholesterol and fatty acid synthesis were quantified. Cytotoxicity was assessed by measuring LDH release. LDL receptor-mediated LDL internalization was measured using a fluorescently labeled LDL probe. [1] |
| Animal Protocol |
Male CD1 mice (n = 5 per group) were administered PF-429242 intraperitoneally every 6 hours for 24 hours at doses of 10 and 30 mg/kg/dose. After 24 hours, hepatic tissues were collected for gene expression analysis and measurement of cholesterol and fatty acid synthesis pathways. [1]
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| ADME/Pharmacokinetics |
In rats, PF-429242 exhibited rapid clearance (CL = 75 mL/min/kg) and poor oral bioavailability (5%). Such high clearance was not predicted in in vitro human liver microsomal studies. [1]
Based on pharmacokinetic models, intraperitoneal injection of 30 mg/kg every 6 hours for 24 hours provides sufficient exposure to assess its acute (24-hour) in vivo efficacy. [1] |
| Toxicity/Toxicokinetics |
In Hep-G2 cells, concentrations of PF-429242 up to 10 µM did not induce cytotoxicity, as determined by an LDH release assay. [1]
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| References | |
| Additional Infomation |
PF-429242 is an aminopyrrolidine amide derivative that was identified as a highly potent and selective S1P inhibitor through high-throughput screening. It is one of the first reported small-molecule S1P inhibitors. [1]
This compound inhibits S1P-mediated SREBP cleavage, a key transcription factor that regulates genes involved in cholesterol and fatty acid metabolism. This mechanism provides a potential strategy for simultaneously inhibiting cholesterol and fatty acid synthesis pathways. [1] PF-429242 was selected from a range of analogs for further evaluation due to its reasonable activity, low molecular weight, and low lipophilicity compared to other highly potent compounds. The active enantiomer (PF-429242) was identified as the R configuration. [1] This study suggests that S1P inhibition is an attractive therapeutic target for treating dyslipidemia and cardiovascular metabolic risk factors associated with cholesterol and fatty acid metabolism disorders. [1] |
| Molecular Formula |
C25H35N3O2
|
|---|---|
| Molecular Weight |
409.5643
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| Exact Mass |
409.272
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| Elemental Analysis |
C, 73.31; H, 8.61; N, 10.26; O, 7.81
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| CAS # |
947303-87-9
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| Related CAS # |
PF429242 dihydrochloride; 2248666-66-0
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| PubChem CID |
23661637
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| Appearance |
Solid powder
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| Density |
1.1±0.1 g/cm3
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| Boiling Point |
562.2±50.0 °C at 760 mmHg
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| Flash Point |
293.8±30.1 °C
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| Vapour Pressure |
0.0±1.5 mmHg at 25°C
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| Index of Refraction |
1.586
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| LogP |
2.88
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
10
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| Heavy Atom Count |
30
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| Complexity |
503
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| Defined Atom Stereocenter Count |
1
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| SMILES |
N([C@H]1CNCC1)(CCC1C=CC=CC=1OC)C(C1C=CC(CN(CC)CC)=CC=1)=O
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| InChi Key |
XKPJTOHUPQWSOJ-HSZRJFAPSA-N
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| InChi Code |
InChI=1S/C25H35N3O2/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/t23-/m1/s1
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| Chemical Name |
4-(diethylaminomethyl)-N-[2-(2-methoxyphenyl)ethyl]-N-[(3R)-pyrrolidin-3-yl]benzamide
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| Synonyms |
PF 429242; PF-429242; PF429242
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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: ~82 mg/mL (~200.2 mM)
Water: ~82 mg/mL Ethanol: ~82 mg/mL |
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| 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 | 2.4416 mL | 12.2082 mL | 24.4164 mL | |
| 5 mM | 0.4883 mL | 2.4416 mL | 4.8833 mL | |
| 10 mM | 0.2442 mL | 1.2208 mL | 2.4416 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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