Synthesis and structure–activity relationship of a novel, achiral series of TNF-α converting enzyme inhibitors

A novel series of achiral TNF-α converting enzyme (TACE) inhibitors has been discovered. These compounds exhibited activities from 0.35 to 11 nM in a porcine TACE assay and inhibited TNF-α production in an LPS-stimulated whole blood assay with an IC50 value of 23 nM for the most potent one. They also have excellent selectivities over related metalloproteases including aggrecanases.

Graphical abstractSeveral series of cyclic-β-aminohydroxamic acids have been synthesized and evaluated for activity against TNF-α-converting enzyme (TACE). The most promising compound exhibits a Ki of 0.35 nM in a pTACE assay and a whole blood activity of 150 nM.Figure optionsDownload full-size imageDownload as PowerPoint slide