Discovery of Novel Hydroxamates as Highly Potent Tumor Necrosis Factor-α Converting Enzyme Inhibitors: Part IDiscovery of Two Binding Modes
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- 作者：Zhaoning Zhu ; Robert Mazzola ; Lisa Sinning ; Brian McKittrick ; Xiaoda Niu ; Daniel Lundell ; Jing Sun ; Peter Orth ; Zhuyan Guo ; Vincent Madison ; Richard Ingram ; Brian M. Beyer
- 刊名：Journal of Medicinal Chemistry
- 出版年：2008
- 出版时间：February 28, 2008
- 年：2008
- 卷：51
- 期：4
- 页码：725 - 736
- 全文大小：835K
- 年卷期：v.51,no.4(February 28, 2008)
- ISSN：1520-4804
文摘
Through a de novo design approach, hydroxamates derived from trans-cyclopropyl dicarboxylate were examined as potential TNF-α converting enzyme (TACE) inhibitors. Two distinctive series of inhibitors (A and B) were identified and shown to have different structure−activity relationship trends and selectivity profiles against other matrix metalloproteases despite their close structural similarities. X-ray crystallography of the inhibitors binding to the TACE enzyme demonstrates that each series derives its activity from the opposite enantiomer of the cyclopropyl scaffolds, which display almost superimposable hydroxamate groups that coordinate to the zinc at the catalytic site. Mode A inhibitors occupy the S1′−S3′ binding pockets, whereas mode B resides in the nonprime binding sites.