Abstract
Matrix metalloproteinase inhibitors of general formula (1) were synthesised by a route involving an Ireland-Claisen rearrangement which enables systematic modification of the substituent alpha to the hydroxamic acid. An analogue (12c) possessing an alpha-cyclopentyl group is a potent broad spectrum inhibitor that displays high and sustained blood levels following oral dosing in both the rat and marmoset ex-vivo bioassays. This compound and analogues are also potent inhibitors of TNF alpha release.
MeSH terms
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Administration, Oral
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Animals
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Biological Availability
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Callithrix
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Depression, Chemical
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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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Lipopolysaccharides / antagonists & inhibitors
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Lipopolysaccharides / pharmacology
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Metalloendopeptidases / 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
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
Substances
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Hydroxamic Acids
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Lipopolysaccharides
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Protease Inhibitors
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Tumor Necrosis Factor-alpha
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Metalloendopeptidases