基于哌啶酸的选择性肿瘤坏死因子-α转化酶（TACE）抑制剂的合成及生物活性
Synthesis and biological activity of selective pipecolic acid-based TNF-alpha converting enzyme (TACE) inhibitors.
作者信息
Letavic Michael A, Axt Matt Z, Barberia John T, Carty Thomas J, Danley Dennis E, Geoghegan Kieran F, Halim Nadia S, Hoth Lise R, Kamath Ajith V, Laird Ellen R, Lopresti-Morrow Lori L, McClure Kim F, Mitchell Peter G, Natarajan Vijayalakshmi, Noe Mark C, Pandit Jayvardhan, Reeves Lisa, Schulte Gayle K, Snow Sheri L, Sweeney Francis J, Tan Douglas H, Yu Chul H
机构信息
Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton, CT 06340, USA.
出版信息
Bioorg Med Chem Lett. 2002 May 20;12(10):1387-90. doi: 10.1016/s0960-894x(02)00183-x.
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.
描述了一系列基于4-羟基和5-羟基哌啶酸异羟肟酸支架的新型选择性肿瘤坏死因子-α转换酶（TACE）抑制剂。与酶的S1'位点相互作用的磺酰胺基团的性质极大地影响了TACE抑制的效力和选择性。取代的4-苄氧基苯磺酰胺表现出优异的TACE效力，对基质金属蛋白酶-1（MMP-1）抑制的选择性大于100倍。苄基醚部分邻位上的烷基取代基对脂多糖处理的人全血中肿瘤坏死因子-α释放的抑制作用最强。
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