Abstract
Matrix metalloproteinase-12 (MMP-12) can be considered an attractive target to study selective inhibitors useful in the development of new therapies for lung and cardiovascular diseases. In this study, a new series of arylsulfonamide carboxylates, with increased hydrophilicity resulting from conjugation with a β-N-acetyl-d-glucosamine moiety, were designed and synthesized as MMP-12 selective inhibitors. Their inhibitory activity was evaluated on human MMPs by using the fluorimetric assay, and a crystallographic analysis was performed to characterize their binding mode. Among these glycoconjugates, a nanomolar MMP-12 inhibitor with improved water solubility, compound 3 [(R)-2-(N-(2-(3-(2-acetamido-2-deoxy-β-d-glucopyranosyl)thioureido)ethyl)biphenyl-4-ylsulfonamido)-3-methylbutanoic acid], was identified.
Keywords:
MMP-12 inhibitors; carbohydrates; drug discovery; glycoconjugates; metalloproteins.
© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylglucosamine / analogs & derivatives*
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Acetylglucosamine / chemical synthesis
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Acetylglucosamine / chemistry
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Catalytic Domain
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Glucosides / chemical synthesis*
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Glucosides / chemistry
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Humans
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Matrix Metalloproteinase 12 / chemistry*
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Matrix Metalloproteinase 9 / chemistry
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Matrix Metalloproteinase Inhibitors / chemical synthesis*
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Matrix Metalloproteinase Inhibitors / chemistry
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Solubility
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Sulfonamides / chemical synthesis*
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Sulfonamides / chemistry
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Thiourea / analogs & derivatives
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Thiourea / chemical synthesis
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Thiourea / chemistry
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Triazoles / chemical synthesis
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Triazoles / chemistry
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Water / chemistry
Substances
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2-(N-(2-(3-(2-acetamido-2-deoxyglucopyranosyl)thioureido)ethyl)biphenyl-4-ylsulfonamido)-3-methylbutanoic acid
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Glucosides
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Matrix Metalloproteinase Inhibitors
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Sulfonamides
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Triazoles
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Water
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MMP9 protein, human
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Matrix Metalloproteinase 9
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MMP12 protein, human
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Matrix Metalloproteinase 12
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Thiourea
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Acetylglucosamine