Duan James J-W, Lu Zhonghui, Xue Chu-Biao, He Xiaohua, Seng Jennifer L, Roderick John J, Wasserman Zelda R, Liu Rui-Qin, Covington Maryanne B, Magolda Ronald L, Newton Robert C, Trzaskos James M, Decicco Carl P
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA.
Bioorg Med Chem Lett. 2003 Jun 16;13(12):2035-40. doi: 10.1016/s0960-894x(03)00313-5.
New inhibitors of tumor necrosis factor-alpha converting enzyme (TACE) were discovered using an N-hydroxy-2-(2-oxo-3-pyrrolidinyl)acetamide scaffold. The series was found to be potent in a porcine TACE (pTACE) assay with IC(50)s typically below 5 nM. For most compounds, selectivity for pTACE relative to MMP-1,-2, and -9 is at least 300-fold. Compound 2o was potent in inhibition of TNFalpha production in a human whole blood assay (WBA) with an IC(50) of 0.42 micro M.
利用N-羟基-2-(2-氧代-3-吡咯烷基)乙酰胺支架发现了肿瘤坏死因子-α转换酶(TACE)的新型抑制剂。该系列化合物在猪TACE (pTACE)检测中表现出强效,半数抑制浓度(IC50)通常低于5 nM。对于大多数化合物,相对于基质金属蛋白酶-1、-2和-9,对pTACE的选择性至少为300倍。化合物2o在人全血检测(WBA)中对肿瘤坏死因子-α产生的抑制作用很强,IC50为0.42 μM。