Tumor necrosis factor-a-converting enzyme

PACE Tumor necrosis factor-a converting enzyme ... 

Sheppeck JE, Gilmore JL, Yang A et al (2007) Discovery of novel hydantoins as selcective non-hydroxamate inhibitors of tumor necrosis factor-a converting enzyme (TACE). Bioorg Med Chem Lett 17 1413-1417... 

H Hydroxamic acids High chelating power Histone deacetylase inhibitors Matrix metalloproteinases inhibitors Tumor necrosis factor a converting enzyme Almquist et aV Massa el Lu el al. Remiszewski et al., Plumb et a(., Kelly et Buggy et al. Hanessian et al. Aranapakam et Noe et al. Duan et... 

Amino sulfonamides are readily condensed with formaldehyde to produce 3,4-dihydro-2//-l-thia-2,4-diazine 1,1-dioxides application affords 219, which was studied as a potential thrombin inhibitor <2003BML1441> while benzo derivative 220 was used as a precursor to potentially selective inhibitors of tumor necrosis factor-a-converting enzyme <2003JME1811>. 

Conversely, in the synthesis of Tumor Necrosis Factor-a Converting Enzyme (TACE) inhibitors, Chemey et al. [40] found that O-arylation occurred in the presence of the more hindered secondary aniline (Scheme 5.23). Arylation of secondary aniline, if it occurred, would have been <5%. This is another example of the copper-promoted N-arylation reaction being very sensitive to steric effects. 

Montero JC, Yuste L, Diaz-Rodriguez E, Esparis-Ogando A, Pandiella A. 2000. Differential shedding of transmembrane neuregulin isoforms by the tumor necrosis factor-alpha-converting enzyme. Mol Cell Neurosci 16 631-648. 

Sheppeck, J. E., II, Gilmore, J. L., Tebben, A., et al. (2007) Hydantoins, triazolones, and imid-azolones as selective non-hydroxamate inhibitors of tumor necrosis factor-oc converting enzyme (TACE). Bioorganic Medicinal Chemistry Letters, 17, 2769-2774. 

This superfamily is named after Astacus protease, or astacin, which was identified as a Zn protease in 1988. The consensus Zn -binding site amino-acid sequence within astacin is HExxHxxGxxH, which also was found in some metalloproteinases these were divided into four subclasses, comprising 33 proteases, in this superfamily.Representative structures of enzymes from the four common subfamilies were characterized, i.e., (i) serratia family (ii) snakevenom protease family (hi) MMP family and (iv) / -lactamase family. The tumor necrosis factor o-converting enzyme (TACE) forms a member of the second subgroup. 

Tsou, C. L., Haskell, C. A., and Charo, I. F. (2001). Tumor necrosis factor-alpha-converting enzyme mediates the inducible cleavage of fractalkine. J. Biol. Chem. 276, 44622-44626. 

APP = Amyloid Precursor Protein, P97 = mellanotransferrin, PS-1 == Presenillin-1 and PS-2 = Presenillin-2, ADAM-10 = A Disintegrin and Metalloprotease Domain-10, and ADAM-17 = = A Disintegrin and Metalloprotease Domain 17, TACE-1 = Tumor Necrosis Factor alpha Converting Enzyme, ORF = Open Reading Frame. 

Spiro hydantoins such as 225-227 (Table 19) were tested for their inhibitory activity against tumor necrosis factor a (TNF-a) converting enzyme (TACE) [82]. The compounds exhibited strong inhibitory activity against porcine TACE and excellent selectivity over MMPs (Table 11). For compound 226, the (55, 6R) enantiomer was more than 80-fold less active against pTACE. Boc or isopropylacetyl pyrrolidine derivatives of 227 were also equipotent with 227. 

IL-1 is stable, and it diffuses to and activates receptors (IL-1 receptors) on adjacent and distant cells. The IL-1 receptor of endothelial cells is especially important (Fig. 13.5a). In all cells, the IL-1 ligand bound to its receptor causes surface expression of a second cytokine, tumor necrosis factor-a (TNF-a). TNF-a was originally described as a factor that kills (causes necrosis of) mouse fibrosarcoma (cancer) cells but not normal mouse fibroblasts. TNF-a is released from the cell surface by an adamalysin protease, TNF alpha converting enzyme (TACE). TACE is also known as ADAM 17, one of more than 40 cell surface bound adamalysins related to the ADAM-TS2 subfamily (Sect. 8.2.1). Unlike IL-1, TNF-a is unstable and can only activate TNF receptors on nearby cells. It usually produces responses that supplement those from IL-1 activation (Fig. 13.5b). 

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