Abstract
Phosphinic acid-based inhibitors of MMP-13 have been investigated with the aim of identifying potent inhibitors with high selectivity versus MMP-1. Independent variation of the substituents on a P(1)' phenethyl group and a P(2) benzyl group improved potencies in both cases around 3-fold over the unsubstituted parent. Combining improved P(1)' and P(2) groups into a single molecule gave an inhibitor with a 4.5 nM IC(50) against MMP-13 and which is 270-fold selective over MMP-1.
MeSH terms
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Collagenases / chemistry
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Indicators and Reagents
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Isomerism
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Matrix Metalloproteinase 1 / chemistry
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Matrix Metalloproteinase 1 / drug effects*
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Matrix Metalloproteinase 13
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Matrix Metalloproteinase 3 / chemistry
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Matrix Metalloproteinase 3 / drug effects*
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Matrix Metalloproteinase Inhibitors*
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Phosphinic Acids / chemistry*
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Phosphinic Acids / pharmacology*
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Protease Inhibitors / chemical synthesis*
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Protease Inhibitors / pharmacology*
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Structure-Activity Relationship
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Substrate Specificity
Substances
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Indicators and Reagents
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Matrix Metalloproteinase Inhibitors
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Phosphinic Acids
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Protease Inhibitors
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Collagenases
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Matrix Metalloproteinase 13
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Matrix Metalloproteinase 3
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Matrix Metalloproteinase 1