肿瘤坏死因子-α转化酶（TACE）低纳摩尔非羟肟酸抑制剂的发现。
Discovery of low nanomolar non-hydroxamate inhibitors of tumor necrosis factor-alpha converting enzyme (TACE).
作者信息
Duan James J-W, Chen Lihua, Lu Zhonghui, Jiang Bin, Asakawa Naoyuki, Sheppeck James E, Liu Rui-Qin, Covington Maryanne B, Pitts William, Kim Soong-Hoon, Decicco Carl P
机构信息
Department of Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA.
出版信息
Bioorg Med Chem Lett. 2007 Jan 1;17(1):266-71. doi: 10.1016/j.bmcl.2006.09.048. Epub 2006 Oct 5.
Using a pyrimidine-2,4,6-trione motif as a zinc-binding group, a series of selective inhibitors of tumor necrosis factor-alpha converting enzyme (TACE) was discovered. Optimization of initial lead 1 resulted in a potent inhibitor (51), with an IC(50) of 2 nM in a porcine TACE assay. To the best of our knowledge, compound 51 and related analogues represent first examples of non-hydroxamate-based inhibitors of TACE with single digit nanomolar potency.
利用嘧啶 -2,4,6 -三酮基序作为锌结合基团，发现了一系列肿瘤坏死因子-α转化酶（TACE）的选择性抑制剂。对初始先导化合物1进行优化得到了一种强效抑制剂（51），在猪TACE测定中IC(50)为2 nM。据我们所知，化合物51及相关类似物代表了具有个位数纳摩尔效力的非异羟肟酸酯类TACE抑制剂的首个实例。
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