PKF 242-484
PKF 242-484 (TNF484) is an orally active dual inhibitor of TACE/MMPs, with Ki values of 3.6, 0.1, 0.9, 1, and 4.5 nM against hMMP-1, hMMP-2, hMMP-3, hMMP-9, and hMMP-13, respectively. PKF 242-484 inhibits the enzymatic activities of MMPs and ADAM17, reduces the release of TNF-α, suppresses the proliferation, migration and invasion of cancer cells, and regulates inflammatory cell infiltration and cytokine production. PKF 242-484 can be used in studies related to airway inflammatory diseases such as asthma and chronic obstructive pulmonary disease, intestinal ischemia-reperfusion injury, epilepsy-induced neuronal damage, and hepatocellular carcinoma.
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- CAS No.: 205807-59-6
- Formule: C19H29N3O6
- Masse moléculaire:395.45
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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
- Protocole
- Pureté et documentation
- Références
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Activité biologique
Description
IC50 & Target
[1]|
hMMP-1 3.6 nM (Ki) |
hMMP-2 0.1 nM (Ki) |
hMMP-3 0.9 nM (Ki) |
hMMP-9 1 nM (IC50) |
hMMP-13 4.5 nM (Ki) |
In Vitro
PKF 242-484 (1 µM; 20 min seizure-like activity, 24 h recovery) inhibits the formation of seizure-induced TNFR1-TRADD and TRADD-FADD signaling complexes in primary mouse hippocampal neuron cultures[3].
PKF 242-484 (10 nM; 72 h) inhibits the migration of HepG2 and Bel7402 cells in xCELLigence real-time migration assays[5].
PKF 242-484 (1 μM; 15 days) reduces the relative invasion values of HepG2 and Bel7402 spheroids from 5.17 to 2.23, and from 2.20 to 1.53, respectively[5].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:Primary mouse hippocampal neurons
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Concentration:1 µM
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Incubation Time:20 min seizure-like activity, 24 h recovery
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Result:Reduced seizure-induced LDH release without affecting basal LDH release.
Reduced seizure-induced binding of TNFR1 and FADD to TRADD.
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Cell Line:HepG2; Bel7402
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Concentration:10 nM
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Incubation Time:72 h
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Result:Reduced migration rates to 64.00% and 72.00%, respectively.
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Cell Line:HepG2; Bel7402
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Concentration:1 μM
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Incubation Time:15 days
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Result:Reduced relative invasion values from 5.17 and 2.2 to 2.23 and 1.53, respectively.
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Cell Line:HepG2; Bel7402
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Concentration:1 μM
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Incubation Time:72 h
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Result:Reduced ADAM17 mRNA expression to 61.66% and 58.10% of control, respectively.
In Vivo
PKF 242-484 (1-10 mg/kg; p.o., intranasal; administered twice daily before and after each cigarette smoke exposure; for 3 consecutive days) dose-dependently reduces bronchoalveolar neutrophilia in BALB/c mice when given via p.o., with a 46% reduction at 10 mg/kg, but shows no definite neutrophil-lowering effect in C57BL/6 mice. When administered intranasally, it dose-dependently reduces bronchoalveolar neutrophilia in BALB/c mice, with a 62% reduction at 10 mg/kg, and decreases macrophage counts at this dose; its neutrophil inhibitory effects in C57BL/6 mice are inconsistent.[4]
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:BALB/c (female, 4-5 weeks old, intranasal LPS challenge-induced acute lung inflammation)[1]
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Dosage:3 mg/kg (TNF-α inhibition); 10 mg/kg (inflammatory cell/TNF-α reduction); 30 mg/kg (inflammatory cell/myeloperoxidase/elastase reduction)
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Administration:i.n.; single dose 30 min before LPS challenge; i.n.; two doses 30 min before and 6 hours after LPS challenge; p.o.; single dose 1 hour before LPS challenge
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Result:Completely inhibited LPS-induced TNF-α release into bronchoalveolar lavage fluid at 3 hours post-challenge.
Caused significant, dose-dependent reductions in LPS-induced neutrophil and lymphocyte accumulation in bronchoalveolar lavage fluid at 3 hours post-challenge; macrophage numbers were unaffected.
Produced similar significant reductions in LPS-induced neutrophil, lymphocyte, and TNF-α levels in bronchoalveolar lavage fluid via p.o. or i.n. routes at 3 hours post-challenge.
Caused significant, dose-dependent reductions in LPS-induced neutrophil and lymphocyte accumulation in bronchoalveolar lavage fluid at 24 hours post-challenge; macrophage numbers were unaffected.
Caused significant reductions in LPS-induced myeloperoxidase and elastase activities in bronchoalveolar lavage fluid at 24 hours post-challenge.
Had no effect on any measured parameters at 3 or 24 hours when administered without LPS challenge.
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Animal Model:C57BL/6 (female, 4-5 weeks old, ovalbumin-induced acute allergic lung inflammation)[1]
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Dosage:1, 3, 10 mg/kg
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Administration:i.n.; two doses 15 min before and 3 hours after ovalbumin challenge
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Result:Caused significant, dose-dependent reductions in ovalbumin-induced neutrophil, eosinophil, and lymphocyte accumulation in bronchoalveolar lavage fluid; macrophage numbers were unaffected.
Caused significant reductions in total ovalbumin-induced inflammatory cell counts in bronchoalveolar lavage fluid.
Had no significant effect on ovalbumin-induced IL-5 levels in bronchoalveolar lavage fluid.
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Animal Model:C57BL/6 (male, 8-10 weeks old, intestinal ischemia-reperfusion injury model via superior mesenteric artery occlusion for 60 min followed by reperfusion)[2]
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Dosage:0.1 mg/kg; 1 mg/kg; 10 mg/kg
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Administration:i.v.; single dose 10 min pre-reperfusion
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Result:Reduced serum TNF-α in a dose-dependent manner; at 1 mg/kg, significantly lowered serum TNF-α compared to vehicle-treated reperfused mice; at 10 mg/kg, maximally inhibited serum TNF-α to near sham-operated levels.
Delayed and reduced lethality at 1 mg/kg and 10 mg/kg doses compared to vehicle; all vehicle-treated mice died within 60 min of reperfusion, while 20% of mice treated with 10 mg/kg survived at 120 min post-reperfusion.
Reduced Evans blue extravasation in intestine and lungs to levels significantly lower than vehicle-treated reperfused mice at 10 mg/kg.
Reduced myeloperoxidase activity in intestine and lungs to levels significantly lower than vehicle-treated reperfused mice at 10 mg/kg.
Reduced intestinal hemoglobin concentrations to levels significantly lower than vehicle-treated reperfused mice at 10 mg/kg.
Significantly reduced TNF-α concentrations in intestine and lungs compared to vehicle-treated reperfused mice at 10 mg/kg.
Significantly reduced CXCL1 (KC) and CCL2 (MCP-1) concentrations in intestine and lungs compared to vehicle-treated reperfused mice at 10 mg/kg.
Showed no effect on reperfusion-associated increases in IL-10 concentrations in intestine and lungs at 10 mg/kg.
Prevented the reperfusion-associated increase in MMP-2 and MMP-3 activity in intestinal tissue at 10 mg/kg.
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Animal Model:BALB/C (female, 16-20 g, whole-body cigarette smoke exposure for 3 days, 5 cigarettes per exposure period)[4]
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Dosage:1, 3, 10 mg/kg (p.o.); 1, 3, 10 mg/kg (i.n.)
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Administration:p.o.; twice daily; 3 days; i.n.; twice daily; 3 days
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Result:Reduced cigarette smoke-induced bronchoalveolar lavage (BAL) neutrophilia dose-dependently, with the 10 mg/kg oral dose producing a 46% reduction.
Reduced BAL neutrophilia dose-dependently, with the 10 mg/kg intranasal dose producing a 62% reduction.
Reduced BAL macrophage numbers at 10 mg/kg intranasal dose compared with smoke-exposed vehicle controls.
Showed no dose-dependent effect on BAL macrophages when administered orally.
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Animal Model:C57BL/6 (female, 16-20 g, whole-body cigarette smoke exposure for 3 days, 4 cigarettes per exposure period)[4]
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Dosage:0.5, 1.5, 5 mg/kg (p.o.); 1, 3, 10 mg/kg (i.n.)
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Administration:p.o.; twice daily; 3 days; i.n.; twice daily; 3 days
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Result:Showed no effect on cigarette smoke-induced BAL neutrophilia when administered orally.
Reduced BAL macrophages at the 0.5 mg/kg oral dose, with higher doses trending toward increasing macrophage numbers.
Showed no consistent dose-dependent effect on BAL neutrophilia when administered intranasal, with a single significant reduction at 3 mg/kg not replicated in a repeat study.
Reduced BAL macrophage numbers back to control levels at the 10 mg/kg intranasal dose.
Chemical Information
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CAS No. 205807-59-6
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Masse moléculaire 395.45
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Formule C19H29N3O6
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SMILES
ONC([C@@H](CO)[C@@H](C1=CC=C(C=C1)OC)C(N[C@@H](C(C)(C)C)C(NC)=O)=O)=O
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Synonyms
TNF484
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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]. Trifilieff A, et al. Pharmacological profile of PKF242-484 and PKF241-466, novel dual inhibitors of TNF-alpha converting enzyme and matrix metalloproteinases, in models of airway inflammation. British journal of pharmacology. 2002 Apr;135(7):1655-64. [Content Brief]
[2]. Souza DG, et al. Effects of PKF242-484 and PKF241-466, novel dual inhibitors of TNF-alpha converting enzyme and matrix metalloproteinases, in a model of intestinal reperfusion injury in mice. European journal of pharmacology. 2007 Sep 24;571(1):72-80. [Content Brief]
[3]. Thompson SJ et al. Suppression of TNF receptor-1 signaling in an in vitro model of epileptic tolerance. Int J Physiol Pathophysiol Pharmacol. 2011;3(2):120-132. [Content Brief]
[4]. Morris A, et al. Comparison of cigarette smoke-induced acute inflammation in multiple strains of mice and the effect of a matrix metalloproteinase inhibitor on these responses. The Journal of pharmacology and experimental therapeutics. 2008 Dec;327(3):851-62. [Content Brief]
[5]. Xia C, et al. Inhibition of hepatocellular carcinoma cell proliferation, migration, and invasion by a disintegrin and metalloproteinase-17 inhibitor TNF484. Journal of research in medical sciences : the official journal of Isfahan University of Medical Sciences. 2019;24:26. [Content Brief]
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
PKF 242-484 Related Classifications
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