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.

Several 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 as PowerPoint slide