Abstract
Aggrecanase-1 and -2 (ADAMTS-4 and ADAMTS-5) are zinc metalloproteases involved in the degradation of aggrecan in cartilage. Inhibitors could provide a means of altering the progression of osteoarthritis. We report the identification of 7 which had good oral pharmacokinetics in rats and showed efficacy in a rat chemical model of osteoarthritis. The projected human dose required to achieve sustained plasma levels ≥10 times the hADAMTS-5 IC50 is 5 mg q.d.
MeSH terms
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ADAMTS4 Protein / antagonists & inhibitors*
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ADAMTS4 Protein / metabolism
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ADAMTS5 Protein / antagonists & inhibitors*
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ADAMTS5 Protein / metabolism
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Aggrecans / metabolism
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Animals
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Enzyme Inhibitors / blood
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacology
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Enzyme Inhibitors / therapeutic use*
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Humans
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Hydantoins / blood
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Hydantoins / chemistry*
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Hydantoins / pharmacology
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Hydantoins / therapeutic use*
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Male
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Molecular Docking Simulation
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Osteoarthritis / drug therapy*
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Osteoarthritis / enzymology
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Osteoarthritis / metabolism
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Rats
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Rats, Inbred Lew
Substances
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Aggrecans
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Enzyme Inhibitors
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Hydantoins
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ADAMTS5 Protein
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ADAMTS4 Protein