Discovery of selective phosphonamide-based inhibitors of tumor necrosis factor-α converting enzyme (TACE)

A novel series of phosphonamide-based inhibitors of tumor necrosis factor-α converting enzyme (TACE) was discovered by structural modification of tetrahydroisoquinoline derivative 1b, which was extremely weak inhibitor of TACE. (S)-Isomer at the phosphorus atom (7b) displayed potent inhibition for TACE, while selectivity sparing MMP-1, -3, and -9.