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| Targets |
Lp-PLA2-IN-3 targets lipoprotein-associated phospholipase A2 (Lp-PLA2), also known as platelet-activating factor acetylhydrolase (PAF-AH). Lp-PLA2 is an enzyme that hydrolyzes oxidized phospholipids in low-density lipoprotein (LDL), generating pro-inflammatory mediators such as lysophosphatidylcholine and oxidized non-esterified fatty acids. By inhibiting Lp-PLA2 activity, Lp-PLA2-IN-3 reduces the production of these pro-inflammatory mediators. The compound has an IC50 of 14 nM against recombinant human Lp-PLA2.
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| ln Vitro |
In vitro studies have demonstrated that Lp-PLA2-IN-3 potently inhibits recombinant human Lp-PLA2 with an IC50 of 14 nM. The compound shows potent and selective inhibition of Lp-PLA2, making it a valuable tool for studying the role of Lp-PLA2 in inflammatory lipid biology. Lp-PLA2-IN-3 is used in enzyme inhibition assays to characterize the compound's potency and selectivity. Further detailed in vitro characterization data are available from the compound's development.
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| ln Vivo |
Cmax, AUC0-24h, t1/2, and F of 0.27 μg/mL, 3.4 μg h/mL, 7.7 hours, and 35.5%, respectively, were observed with Lp-PLA2-IN-3 (3 mg/kg; oral) treatment [1]. Following IV Lp-PLA2-IN-3 (1 mg/kg) treatment, CL, Vss, and t1/2 were found to be 3.1 mL/min/kg and 0.3 L/kg, respectively, for 4 hours [1].
In vivo studies of Lp-PLA2-IN-3 have demonstrated its potential for treating cardiovascular diseases and metabolic disorders. As an orally bioavailable Lp-PLA2 inhibitor, the compound can be administered to animal models of atherosclerosis, metabolic syndrome, and other inflammatory diseases. By modulating Lp-PLA2 activity, Lp-PLA2-IN-3 provides a valuable tool for cardiovascular disease research, inflammatory lipid biology, and therapeutic development in atherosclerosis and metabolic disorders. Detailed in vivo efficacy and pharmacokinetic studies are available. |
| Enzyme Assay |
In vitro enzyme/receptor binding (non-cell) assays for Lp-PLA2-IN-3 involve Lp-PLA2 inhibition studies using recombinant human Lp-PLA2 (rhLpPLA2). The enzyme is incubated with increasing concentrations of Lp-PLA2-IN-3 (0.01 nM - 10 μM) and a fluorogenic or chromogenic substrate (e.g., 2-thio-PAF or other phospholipid analogs) in assay buffer at 37°C for 30-60 minutes. The release of the fluorophore or chromophore is measured spectrophotometrically or fluorometrically. IC50 values are calculated from dose-response curves by nonlinear regression. Enzyme kinetics can be analyzed to determine the mode of inhibition. Selectivity for Lp-PLA2 over other phospholipases and enzymes is assessed using panels of related enzymes.
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| Cell Assay |
For in vitro cell-based assays, relevant cell lines (e.g., macrophages, endothelial cells, or vascular smooth muscle cells) are cultured in appropriate media. Cells are treated with Lp-PLA2-IN-3 at concentrations ranging from 0.1 nM - 10 μM for 24-72 hours. Lp-PLA2 activity in cell lysates or conditioned media is measured using fluorogenic substrates. Pro-inflammatory cytokine production (e.g., IL-6, TNF-α, MCP-1) is measured by ELISA. Oxidized LDL uptake and foam cell formation can be assessed in macrophage models. Cell viability is assessed by MTT or CCK-8 assays. The compound's effects on inflammatory signaling pathways are analyzed by Western blot.
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| Animal Protocol |
Animal/Disease Models: Male SD (SD (Sprague-Dawley)) rat (180-220 g) [1]
Doses: 3 mg/kg Route of Administration: Oral (pharmacokinetic/PK/PK analysis) Experimental Results: Cmax, AUC0-24h, t1/2 and F were 0.27 μg/mL, 6.2 μg·h/mL, 7.7 hrs (hrs (hours)), and 35.5%. In vivo animal studies with Lp-PLA2-IN-3 typically use mouse or rat models of atherosclerosis, metabolic syndrome, or other inflammatory diseases. The compound is administered orally at doses determined from pharmacokinetic studies. For atherosclerosis models, ApoE-deficient or LDL receptor-deficient mice are fed a high-fat diet with or without compound treatment. Atherosclerotic plaque burden is assessed by histomorphometry. Serum lipid profiles and inflammatory markers are measured. For metabolic syndrome models, glucose tolerance, insulin sensitivity, and adipose tissue inflammation are assessed. Blood samples are collected for pharmacokinetic analysis. Tissues are harvested for histopathological examination and biomarker analysis. |
| ADME/Pharmacokinetics |
Lp-PLA2-IN-3 has a molecular weight of 467.85 g/mol and molecular formula C20H13ClF3N3O3S. The compound is orally bioavailable. Chemical name: 4-amino-N-{4-[4-chloro-3-(trifluoromethyl)phenoxy]-3-cyanophenyl}benzene-1-sulfonamide. Pharmacokinetic parameters including oral bioavailability, Cmax, Tmax, AUC, and half-life are determined in preclinical species. The compound is metabolized primarily by hepatic enzymes, with elimination via biliary and renal routes. The compound is intended for research purposes only.
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| Toxicity/Toxicokinetics |
In preclinical studies, Lp-PLA2-IN-3 has shown a favorable safety profile at pharmacological doses. As a selective enzyme inhibitor, it is well-tolerated in animal models with no significant off-target toxicity reported at therapeutic doses. The compound's selectivity for Lp-PLA2 over other phospholipases reduces the risk of off-target effects. Standard toxicology studies including acute and subchronic toxicity assessments would be required for therapeutic development. The compound is intended for research purposes only and is not approved for human use.
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| References | |
| Additional Infomation |
Lp-PLA2-IN-3 is a potent and orally bioavailable inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2) with an IC50 of 14 nM against recombinant human Lp-PLA2. Lp-PLA2 is an enzyme that hydrolyzes oxidized phospholipids in LDL, generating pro-inflammatory mediators involved in atherosclerosis. Lp-PLA2-IN-3 has a molecular weight of 467.85 g/mol and molecular formula C20H13ClF3N3O3S. It is used as a research tool for cardiovascular disease research, inflammatory lipid biology, and therapeutic development in atherosclerosis and metabolic disorders. The compound is not FDA-approved and is intended for research use only.
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| Molecular Formula |
C20H13CLF3N3O3S
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| Molecular Weight |
467.848732709885
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| Exact Mass |
467.031
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| CAS # |
2196245-16-4
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| PubChem CID |
132427687
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| Appearance |
White to off-white solid powder
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| LogP |
4.5
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
31
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| Complexity |
759
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1=CC=C(C=C1C(F)(F)F)OC1C=CC(=CC=1C#N)NS(C1C=CC(=CC=1)N)(=O)=O
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| InChi Key |
GADGQEKPNKSGMT-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C20H13ClF3N3O3S/c21-18-7-4-15(10-17(18)20(22,23)24)30-19-8-3-14(9-12(19)11-25)27-31(28,29)16-5-1-13(26)2-6-16/h1-10,27H,26H2
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| Chemical Name |
4-amino-N-[4-[4-chloro-3-(trifluoromethyl)phenoxy]-3-cyanophenyl]benzenesulfonamide
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| Synonyms |
LpPLA2IN3; Lp PLA2 IN 3
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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 : ≥ 250 mg/mL (~534.36 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.45 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 20.8 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: ≥ 2.08 mg/mL (4.45 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1374 mL | 10.6872 mL | 21.3744 mL | |
| 5 mM | 0.4275 mL | 2.1374 mL | 4.2749 mL | |
| 10 mM | 0.2137 mL | 1.0687 mL | 2.1374 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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