| Abstract
| - The design, synthesis, evaluation, and identification of anovel class of (6S,7S)-N-hydroxy-6-carboxamide-5-azaspiro[2.5]octane-7-carboxamides as the first potent and selective inhibitors of humanepidermal growth factor receptor-2 (HER-2) sheddase is described.Several compounds were identified that possess excellent pharmacodynamic and pharmacokinetic properties and were shown to decreasetumor size, cleaved HER-2 extracellular domain plasma levels, andpotentiate the effects of the humanized anti-HER-2 monoclonal antibody(trastuzumab) in vivo in a HER-2 overexpressing cancer murinexenograft model.
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