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ID: ALA1135115
Journal: Bioorg Med Chem Lett
Title: Synthesis and biological activity of selective pipecolic acid-based TNF-alpha converting enzyme (TACE) inhibitors.
Authors: Letavic MA, Axt MZ, Barberia JT, Carty TJ, Danley DE, Geoghegan KF, Halim NS, Hoth LR, Kamath AV, Laird ER, Lopresti-Morrow LL, McClure KF, Mitchell PG, Natarajan V, Noe MC, Pandit J, Reeves L, Schulte GK, Snow SL, Sweeney FJ, Tan DH, Yu CH.
Abstract: A series of novel, selective TNF-alpha converting enzyme inhibitors based on 4-hydroxy and 5-hydroxy pipecolate hydroxamic acid scaffolds is described. The potency and selectivity of TACE inhibition is dramatically influenced by the nature of the sulfonamide group which interacts with the S1' site of the enzyme. Substituted 4-benzyloxybenzenesulfonamides exhibit excellent TACE potency with >100x selectivity over inhibition of matrix metalloprotease-1 (MMP-1). Alkyl substituents on the ortho position of the benzyl ether moiety give the most potent inhibition of TNF-alpha release in LPS-treated human whole blood.
CiteXplore: 11992783