Abstract
A series of 3-hydroxy-3-methylpipecolic hydroxamate inhibitors of MMP-13 and aggrecanase was designed based on the observation of increased aggrecanase activity with substitution at the 3-position of the piperidine ring. Potency versus aggrecanase was optimized by modification of the benzyloxyarylsulfonamide group that binds in the S1' pocket. These compounds also possess markedly improved bioavailability and lower metabolic clearance compared to analogous 3,3-dimethyl-5-hydroxypipecolic hydroxamates. These improvements are attributed to lowered lipophilicity proximal to the metabolically labile hydroxamic acid. Synthesis, structure activity relationships, and in vivo efficacy data are described.
MeSH terms
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Administration, Oral
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Animals
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Collagenases / metabolism
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Drug Design
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Endopeptidases / drug effects*
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Endopeptidases / metabolism
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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 / pharmacokinetics*
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Matrix Metalloproteinase 13
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Matrix Metalloproteinase Inhibitors*
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Molecular Structure
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Pipecolic Acids / chemical synthesis*
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Pipecolic Acids / chemistry
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Pipecolic Acids / pharmacokinetics*
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Protease Inhibitors / chemical synthesis
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Protease Inhibitors / chemistry
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Protease Inhibitors / pharmacokinetics
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Structure-Activity Relationship
Substances
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Hydroxamic Acids
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Matrix Metalloproteinase Inhibitors
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Pipecolic Acids
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Protease Inhibitors
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Endopeptidases
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Collagenases
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MMP13 protein, human
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Matrix Metalloproteinase 13
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aggrecanase