Abstract
Anti-succinate hydroxamates with cyclic P1 motifs were synthesized as aggrecanase inhibitors. The N-methanesulfonyl piperidine 23 and the N-trifluoroacetyl azetidine 26 were the most potent aggrecanase inhibitors both having an IC(50)=3nM while maintaining >100-fold selectivity over MMP-1, -2, and -9. The cyclic moieties were also capable of altering in vivo metabolism, hence delivering low clearance compounds in both rat and dog studies as shown for compound 14.
MeSH terms
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Animals
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Cattle
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Dogs
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Endopeptidases / metabolism*
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Half-Life
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Hydroxamic Acids / chemical synthesis*
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Hydroxamic Acids / pharmacokinetics
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Hydroxamic Acids / pharmacology*
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Indicators and Reagents
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Isoenzymes / antagonists & inhibitors
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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
Substances
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Hydroxamic Acids
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Indicators and Reagents
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Isoenzymes
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Protease Inhibitors
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Endopeptidases
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aggrecanase