Abstract
A series of 1-sulfonylaminocyclopropanecarboxylates was synthesized as ADAMTS-5 (Aggrecanase-2) inhibitors. After an intensive investigation of the central cyclopropane core including its absolute stereochemistry and substituents, we found compound 22 with an Agg-2 IC50=7.4 nM, the most potent ADAMTS-5 inhibitor reported so far.
MeSH terms
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ADAM Proteins / antagonists & inhibitors*
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ADAM Proteins / metabolism
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ADAMTS5 Protein
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Animals
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Binding Sites
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Computer Simulation
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Cyclopropanes / chemical synthesis*
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Cyclopropanes / chemistry
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Cyclopropanes / pharmacokinetics
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Cyclopropanes / pharmacology
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Drug Design
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Humans
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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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Protein Binding
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Rats
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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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Cyclopropanes
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Protease Inhibitors
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Sulfonamides
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cyclopropanecarboxylic acid
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ADAM Proteins
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ADAMTS5 Protein
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ADAMTS5 protein, human