1. Matrix metalloproteinase inhibitors containing a (carboxyalkyl)amino zinc ligand: modification of the P1 and P2' residues.
- Author
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Brown FK, Brown PJ, Bickett DM, Chambers CL, Davies HG, Deaton DN, Drewry D, Foley M, McElroy AB, and Gregson M
- Subjects
- Amino Acid Sequence, Chromogenic Compounds metabolism, Dipeptides chemical synthesis, Dipeptides pharmacology, Drug Stability, Fluorescent Dyes, Gelatinases antagonists & inhibitors, Half-Life, Humans, Hydrogen-Ion Concentration, Indoles chemical synthesis, Indoles pharmacology, Isoindoles, Matrix Metalloproteinase 3, Matrix Metalloproteinase Inhibitors, Molecular Sequence Data, Molecular Structure, Structure-Activity Relationship, Dipeptides chemistry, Extracellular Matrix enzymology, Indoles chemistry, Metalloendopeptidases antagonists & inhibitors, Zinc
- Abstract
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.
- Published
- 1994
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