Abstract
An extensive study of the requirements for effective binding of N-carboxyalkyl peptides to human stromelysin, collagenase, and to a lesser extent, gelatinase A has been investigated. These efforts afforded inhibitors generally in the 100-400 nM range for these matrix metalloproteinases. The most significant increase in potency was obtained with the introduction of a beta-phenylethyl group at the P1' position, suggesting a small hydrophobic channel into the S1' subsite of stromelysin. One particular compound, N-[1(R)-carboxyethyl]-alpha(S)-(2-phenylethyl)glycyl-L-leucine,N- phenylamide (79a), is relatively selective for rabbit stromelysin with a K(i) = 6.5 nM and may prove useful for elucidating the role of endogenously-produced stromelysin in lapine models of tissue degradation.
MeSH terms
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Amino Acid Sequence
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Animals
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Blood
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Collagenases / metabolism
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Dipeptides / chemical synthesis*
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Dipeptides / metabolism
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Dipeptides / pharmacology
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Drug Stability
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Extracellular Matrix / enzymology*
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Fibroblasts / enzymology
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Gelatinases / antagonists & inhibitors
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Gelatinases / metabolism
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Humans
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Hydrogen-Ion Concentration
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Matrix Metalloproteinase 2
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Matrix Metalloproteinase 3
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Matrix Metalloproteinase Inhibitors
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Metalloendopeptidases / antagonists & inhibitors*
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Metalloendopeptidases / metabolism
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Mice
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Molecular Sequence Data
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Molecular Structure
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Rabbits
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Structure-Activity Relationship
Substances
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Dipeptides
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Matrix Metalloproteinase Inhibitors
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N-(1-carboxyethyl)-alpha-(2-phenylethyl)glycyl-leucine, N-phenylamide
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Collagenases
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Gelatinases
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Metalloendopeptidases
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Matrix Metalloproteinase 3
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Matrix Metalloproteinase 2