Matrix metalloproteinase inhibitors containing a (carboxyalkyl)amino zinc ligand: modification of the P1 and P2' residues.
Systematic modification of the presumed P1 side chain in a series of (carboxyalkyl)amino-based inhibitors of matrix metalloproteinases enabled identification of the 2-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)ethyl group as a preferred substituent imparting potent inhibition of the enzymes collagenase and gelatinase. It was subsequently found that the P2'-P3' residues in this series could be replaced by small non-peptide residues, while maintaining inhibitory potency. The imide group in this series of compounds can undergo autocatalytic hydrolysis under neutral conditions.
Brown
F K
FK
Glaxo Incorporated Research Institute, Research Triangle Park, North Carolina 27709.
Brown
P J
PJ
Bickett
D M
DM
Chambers
C L
CL
Davies
H G
HG
Deaton
D N
DN
Drewry
D
D
Foley
M
M
McElroy
A B
AB
Gregson
M
M
D000595:Amino Acid Sequence; D002863:Chromogenic Compounds / Q000378:metabolism; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004355:Drug Stability; D005109:Extracellular Matrix / Q000201:enzymology*; D005456:Fluorescent Dyes; D018093:Gelatinases / Q000037:antagonists & inhibitors; D006207:Half-Life; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D054833:Isoindoles; D019278:Matrix Metalloproteinase 3; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D008969:Molecular Sequence Data; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D015032:Zinc
D002863:Chromogenic Compounds; D004151:Dipeptides; D005456:Fluorescent Dyes; D007211:Indoles; D054833:Isoindoles; D061965:Matrix Metalloproteinase Inhibitors; C086216:(N-(1-carboxy-3-(1,3-dihydro-1,3-dioxo-2H-benz(f)isoindol-2-yl)propyl)-leucyl)-N-methyl-phenylalaninamide; D018093:Gelatinases; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3; D015032:Zinc