Abstract
Starting from a potent pantolactone ketoamide cathepsin K inhibitor discovered from structural screening, conversion of the lactone scaffold to a pyrrolidine scaffold allowed exploration of the S(3) subsite of cathepsin K. Manipulation of P3 and P1' groups afforded potent inhibitors with drug-like properties.
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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Binding Sites
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Cathepsin K
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Cathepsins / antagonists & inhibitors*
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Cathepsins / chemistry
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Crystallography, X-Ray
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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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Humans
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Inhibitory Concentration 50
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Ketones* / chemical synthesis
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Ketones* / pharmacokinetics
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Ketones* / pharmacology
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Models, Molecular
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Molecular Structure
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Pyrrolidines* / chemical synthesis
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Pyrrolidines* / pharmacokinetics
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Pyrrolidines* / pharmacology
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Serine Proteinase Inhibitors
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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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Pyrrolidines
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Serine Proteinase Inhibitors
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Cathepsins
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CTSK protein, human
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Cathepsin K
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pyrrolidine