Abstract
5'-Phenyl-3'H-spiro[indoline-3,2'-[1,3,4]thiadiazol]-2-one inhibitors of ADAMTS-5 (Aggrecanase-2) have been prepared via commercially available starting materials. Selected compounds 23, 33-35 show sub-micromolar ADAMTS-5 potency and strong SAR trends with selectivity over the related metalloproteases ADAMTS-4 (Aggrecanase-1), MMP12, and MMP13. This series of compounds represents progress toward a selective ADAMTS-5 inhibitor as a disease modifying osteoarthritis drug.
MeSH terms
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Endopeptidases / metabolism*
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Indoles / chemistry*
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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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Spiro Compounds / chemical synthesis
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Spiro Compounds / chemistry*
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Spiro Compounds / pharmacology*
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Structure-Activity Relationship
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Thiadiazoles / chemical synthesis
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Thiadiazoles / chemistry*
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Thiadiazoles / pharmacology
Substances
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Indoles
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Protease Inhibitors
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Spiro Compounds
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Thiadiazoles
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indoline
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Endopeptidases
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aggrecanase