Abstract
The design and synthesis of a series of highly selective hydroxamate inhibitors of stromelysin-1 (MMP-3) is described. Substitution of a 4-biaryl piperidine sulfonamide core, which binds at the S1' subsite of MMP-3, was optimised to give potent inhibitors of MMP-3, with greater than 300-fold selectivity over MMP-1, MMP-2, MMP-9 and MMP-14. Compounds 26 and 27 were identified as having the best balance of pharmacology and properties required for topical drug delivery.
MeSH terms
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Amino Acids / chemistry
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Combinatorial Chemistry Techniques
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Drug Delivery Systems
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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 Inhibitors*
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Models, Molecular
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Molecular Structure
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Protease Inhibitors / chemical synthesis*
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Protease Inhibitors / chemistry
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Protease Inhibitors / pharmacology*
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis*
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Sulfonamides / chemistry
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Sulfonamides / pharmacology*
Substances
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Amino Acids
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Hydroxamic Acids
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Matrix Metalloproteinase Inhibitors
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Protease Inhibitors
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Sulfonamides