Conversion of an MMP-potent scaffold to an MMP-selective HER-2 sheddase inhibitor via scaffold hybridization and subtle P1′ permutations

A series of β-sulfonamide piperidine hydroxamates were prepared and shown to be potent inhibitors of the human epidermal growth factor receptor-2 (HER-2) sheddase with excellent selectivity against MMP-1, −2, −3, and −9. This was achieved by exploiting subtle differences within the otherwise highly conserved S1′ binding pocket of the active sites within the metalloprotease family. In addition, it was discovered that the introduction of polarity to the P1 and P1′ groups reduced the projected human clearance.

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