GW-3333 - CAS 212609-68-2
Catalog number: 212609-68-2
Category: Inhibitor
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Molecular Formula:
C22H36N4O4
Molecular Weight:
420.55
COA:
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Targets:
TNF-alpha
Description:
GW-3333 is a dual inhibitors of tumor necrosis factor-alpha (TNF)-Converting Enzyme (TACE) and matrix metalloproteinases.
Purity:
>98%
Appearance:
Solid powder
Synonyms:
3-[formyl(hydroxy)amino]-4-methyl-N-[3-methyl-1-oxo-1-(pyridin-2-ylamino)pentan-2-yl]-2-(2-methylpropyl)pentanamide;
MSDS:
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InChIKey:
SMZPWUUYPYYHIV-UHFFFAOYSA-N
InChI:
1S/C22H36N4O4/c1-7-16(6)19(22(29)24-18-10-8-9-11-23-18)25-21(28)17(12-14(2)3)20(15(4)5)26(30)13-27/h8-11,13-17,19-20,30H,7,12H2,1-6H3,(H,25,28)(H,23,24,29)
Canonical SMILES:
CCC(C)C(C(=O)NC1=CC=CC=N1)NC(=O)C(CC(C)C)C(C(C)C)N(C=O)O
1.Design of selective and soluble inhibitors of tumor necrosis factor-alpha converting enzyme (TACE).
Rabinowitz MH;Andrews RC;Becherer JD;Bickett DM;Bubacz DG;Conway JG;Cowan DJ;Gaul M;Glennon K;Lambert MH;Leesnitzer MA;McDougald DL;Moss ML;Musso DL;Rizzolio MC J Med Chem. 2001 Nov 22;44(24):4252-67.
A program to improve upon the in vitro, in vivo, and physicochemical properties of N-hydroxyformamide TACE inhibitor GW 3333 (1) is described. Using the primary structure of pro-TNF-alpha, along with a homology model of the catalytic domain of TACE based on the X-ray diffraction coordinates of adamalysin, we synthesized N-hydroxyformamide TACE inhibitors containing a P2' arginine side chain. Introduction of nitro and sulfonyl electron-withdrawing groups covalently bound to the P2' guanidine moiety rendered the inhibitors electronically neutral at cellular pH and led to potent inhibition of TNF-alpha release from stimulated macrophages. Inhibitors containing these arginine mimetics were found to have increased solubility in simulated gastric fluid (SGF) relative to 1, allowing for the incorporation of lipophilic P1' side chains which had the effect of retaining potent TACE inhibition, but reducing potency against matrix metalloproteases (MMPs) thus increasing overall selectivity against MMP1, MMP3, and MMP9. Selected compounds showed good to excellent in vivo TNF inhibition when administered via subcutaneous injection. One inhibitor, 28a, with roughly 10x selectivity over MMP1 and MMP3 and high solubility in SGF, was evaluated in the rat zymosan-induced pleuisy model of inflammation and found to inhibit zymosan-stimulated pleural TNF-alpha elevation by 30%.
2.Inhibition of tumor necrosis factor-alpha (TNF-alpha) production and arthritis in the rat by GW3333, a dual inhibitor of TNF-alpha-converting enzyme and matrix metalloproteinases.
Conway JG;Andrews RC;Beaudet B;Bickett DM;Boncek V;Brodie TA;Clark RL;Crumrine RC;Leenitzer MA;McDougald DL;Han B;Hedeen K;Lin P;Milla M;Moss M;Pink H;Rabinowitz MH;Tippin T;Scates PW;Selph J;Stimpson SA;Warner J;Becherer JD J Pharmacol Exp Ther. 2001 Sep;298(3):900-8.
Tumor necrosis factor-alpha (TNF)-converting enzyme (TACE) cleaves the precursor form of TNF, allowing the mature form to be secreted into the extracellular space. GW3333, a dual inhibitor of TACE and matrix metalloproteinases (MMPs), was compared with an anti-TNF antibody to evaluate the importance of soluble TNF and MMPs in rat models of arthritis. Oral administration of GW3333 completely blocked increases in plasma TNF after LPS for up to 12 h. In a model wherein intrapleural zymosan injection causes an increase in TNF in the pleural cavity, GW3333 completely inhibited the increase in TNF in the pleural cavity for 12 h. Under these dosing conditions, the plasma levels of unbound GW3333 were at least 50-fold above the IC(50) values for inhibition of individual MMPs in vitro. In a model wherein bacterial peptidoglycan polysaccharide polymers reactivate a local arthritis response in the ankle, a neutralizing anti-TNF antibody completely blocked the ankle swelling over the 3-day reactivation period. GW3333 administered b.i.d. over the same period also inhibited ankle swelling, with the highest dose of 80 mg/kg being slightly less active than the anti-TNF antibody. In a 21-day adjuvant arthritis model, the anti-TNF antibody did not inhibit the ankle swelling or the joint destruction, as assessed by histology or radiology.
3.Compounds blocking methylglyoxal-induced protein modification and brain endothelial injury.
Tóth AE;Tóth A;Walter FR;Kiss L;Veszelka S;Ózsvári B;Puskás LG;Heimesaat MM;Dohgu S;Kataoka Y;Rákhely G;Deli MA Arch Med Res. 2014 Nov;45(8):753-64. doi: 10.1016/j.arcmed.2014.10.009. Epub 2014 Nov 13.
BACKGROUND AND AIMS: ;Elevated levels of reactive carbonyl species such as methylglyoxal triggers carbonyl stress and activates a series of inflammatory responses leading to accelerated vascular damage. Carbonyl stress is implicated in conditions and diseases like aging, diabetes mellitus, Alzheimer's disease and cardiovascular diseases. Our aim was to examine the effects of methylglyoxal on human hCMEC/D3 brain endothelial cells and search for protective molecules to prevent endothelial damage.;METHODS: ;Methylglyoxal-induced modification of albumin was tested in a cell-free assay. Endothelial cell viability was monitored by impedance measurement in real-time. The following compounds were tested in cell-free and viability assays: β-alanine, all-trans-retinoic acid, aminoguanidine, ascorbic acid, L-carnosine, GW-3333, indapamide, piracetam, γ-tocopherol, U0126, verapamil. Barrier function of brain endothelial monolayers was characterized by permeability measurements and visualized by immunohistochemistry for β-catenin. mRNA expression level of 60 selected blood-brain barrier-related genes in hCMEC/D3 cells was investigated by a custom Taqman gene array.;RESULTS: ;Methylglyoxal treatment significantly elevated protein modification, exerted toxicity, reduced barrier integrity, increased permeability for markers FITC-dextran and albumin and caused higher production of reactive oxygen species in hCMEC/D3 endothelial cells.
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CAS 212609-68-2 GW-3333

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