Abstract
An orally bioavailable series of ketoamide-based cathepsin K inhibitors with good pharmacokinetic properties has been identified. Starting from a potent inhibitor endowed with poor drug properties, conformational constraint of the P(2)-P(3) linker and modifications to P(1') elements led to an enhancement in potency, solubility, clearance, and bioavailability. These optimized inhibitors attenuated bone resorption in a rat TPTX hypocalcemic bone resorption model.
MeSH terms
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Amides / chemical synthesis*
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Amides / pharmacokinetics
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Amides / pharmacology
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Animals
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Binding Sites
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Biological Availability
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Bone Resorption / drug therapy
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Bone Resorption / metabolism
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Cathepsin K
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Cathepsins / antagonists & inhibitors*
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Cathepsins / chemistry
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Cysteine Proteinase Inhibitors / chemical synthesis*
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Cysteine Proteinase Inhibitors / pharmacokinetics
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Cysteine Proteinase Inhibitors / pharmacology
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Disease Models, Animal
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Hypocalcemia / drug therapy
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Hypocalcemia / metabolism
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Ketones / chemical synthesis*
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Ketones / pharmacokinetics
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Ketones / pharmacology
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Rats
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Rats, Wistar
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Solubility
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Structure-Activity Relationship
Substances
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Amides
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Cysteine Proteinase Inhibitors
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Ketones
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Cathepsins
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Cathepsin K
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Ctsk protein, rat