Abstract
A serendipitous discovery that the metalloprotease binding profile of a novel class of 2-carboxamide-3-hydroxamic acid piperidines could be significantly attenuated by the modification 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.
MeSH terms
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ADAM Proteins / metabolism*
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ADAM10 Protein
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Amyloid Precursor Protein Secretases / metabolism*
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Cell Line, Tumor
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Drug Design
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Humans
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Hydroxamic Acids / chemical synthesis*
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Hydroxamic Acids / chemistry
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Hydroxamic Acids / pharmacology
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Matrix Metalloproteinase 2 / metabolism
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Membrane Proteins / metabolism*
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Protein Binding
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Receptor, ErbB-2 / metabolism*
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Structure-Activity Relationship
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Substrate Specificity
Substances
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Antineoplastic Agents
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Hydroxamic Acids
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Membrane Proteins
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Receptor, ErbB-2
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Amyloid Precursor Protein Secretases
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ADAM Proteins
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Matrix Metalloproteinase 2
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ADAM10 Protein
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ADAM10 protein, human