Discovery of Selective Hydroxamic Acid Inhibitors of Tumor Necrosis Factor-α Converting Enzyme.

Abstract Modification of the P 1 ′ substituent of macrocyclic matrix metalloproteinase (MMP) inhibitors provided compounds that are selective for inhibition of tumor necrosis factor-α converting enzyme (TACE) over MMP-1 and MMP-2. Several analogues potently inhibited the release of TNF-α in a THP-1 cellular assay. Compounds containing a trimethoxyphenyl group in the P 1 ′ substituent demonstrated TACE selectivity across several series of hydroxamate-based inhibitors.