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Conversion of an MMP-potent scaffold to an MMP-selective HER-2 sheddase inhibitor via scaffold hybridization and subtle P-1 ' permutations

, : Conversion of an MMP-potent scaffold to an MMP-selective HER-2 sheddase inhibitor via scaffold hybridization and subtle P-1 ' permutations. Bioorganic and Medicinal Chemistry Letters 18(2): 560-564

A series of beta-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 S-1' binding pocket of the active sites within the metalloprotease family. In addition, it was discovered that the introduction of polarity to the P-1 and P-1' groups reduced the projected human clearance.


DOI: 10.1016/j.bmcl.2007.11.086

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