Compelling P1 Substituent Affect On Metalloprotease Binding Pro. Le Enables The Design Of A Novel Cyclohexyl Core Scaffold With Excellent Mmp Selectivity And Her-2 Sheddase Inhibition

A serendipitous discovery that the metalloprotease binding pro. le of a novel class of 2-carboxamide-3-hydroxamic acid piperidines could be significantly attenuated by the modi. cation of the unexplored P1 substituent enabled the design and synthesis of a novel 2-carboxamide-1-hydroxamic acid cyclohexyl scaffold core that exhibited excellent HER-2 potency and unprecedented MMP-selectivity that we believe would not have been possible via conventional P1' perturbations. (C) 2009 Elsevier Ltd. All rights reserved.