Abstract
In an effort to obtain a MMP selective and potent inhibitor of HER-2 sheddase (ADAM-10), the P1' group of a novel class of (6S,7S)-7-[(hydroxyamino)carbonyl]-6-carboxamide-5-azaspiro[2.5]octane-5-carboxylates was attenuated and the structure-activity relationships (SAR) will be discussed. In addition, it was discovered that unconventional perturbation of the P2' moiety could confer MMP selectivity, which was hypothesized to be a manifestation of the P2' group effecting global conformational changes.
MeSH terms
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ADAM Proteins / antagonists & inhibitors*
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ADAM Proteins / metabolism
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ADAM10 Protein
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Amides / chemical synthesis
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Amides / chemistry
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Amides / pharmacology
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Amyloid Precursor Protein Secretases / antagonists & inhibitors*
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Amyloid Precursor Protein Secretases / metabolism
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Aza Compounds / chemical synthesis
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Aza Compounds / chemistry
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Aza Compounds / pharmacology
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Drug Design
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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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Membrane Proteins / antagonists & inhibitors*
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Membrane Proteins / metabolism
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacology
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Protein Structure, Tertiary
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Receptor, ErbB-2 / antagonists & inhibitors*
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Receptor, ErbB-2 / metabolism
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Spiro Compounds / chemical synthesis
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Spiro Compounds / chemistry
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Spiro Compounds / pharmacology
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Structure-Activity Relationship
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Substrate Specificity
Substances
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Amides
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Aza Compounds
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Hydroxamic Acids
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Membrane Proteins
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Protein Kinase Inhibitors
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Spiro Compounds
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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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ADAM10 Protein
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ADAM10 protein, human