Discovery of low nanomolar non-hydroxamate inhibitors of tumor necrosis factor-alpha converting enzyme (TACE).
James J-W Duan, Lihua Chen, Zhonghui Lu, Bin Jiang, Naoyuki Asakawa, James E Sheppeck, Rui-Qin Liu, Maryanne B Covington, William Pitts, Soong-Hoon Kim, Carl P Decicco
Index: Bioorg. Med. Chem. Lett. 17(1) , 266-71, (2007)
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Abstract
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.
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