Abstract
The synthesis and structure-activity relationship of a series of arylaminoethyl amide cathepsin S inhibitors are reported. Optimization of P3 and P2 groups to improve overall physicochemical properties resulted in significant improvements in oral bioavailability over early lead compounds. An X-ray structure of compound 37 bound to the active site of cathepsin S is also reported.
MeSH terms
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Administration, Oral
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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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Cathepsins / antagonists & inhibitors*
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Crystallography, X-Ray
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Ethers, Cyclic / chemical synthesis
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Ethers, Cyclic / pharmacology
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Humans
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Male
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Molecular Structure
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Protease Inhibitors / chemical synthesis
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Protease Inhibitors / pharmacokinetics
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Protease Inhibitors / pharmacology
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Rats
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Rats, Wistar
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Structure-Activity Relationship
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Zinc
Substances
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Amides
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Ethers, Cyclic
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Protease Inhibitors
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Cathepsins
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cathepsin S
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Zinc