| Abstract
| - A series of phosphonamide-based hydroxamate derivatives were synthesized, and the inhibitoryactivities were evaluated against various metalloproteinases in order to clarify its selectivityprofile. Among the four diastereomeric isomers resulting from the chirality at the C-3 and Patoms, the compound with a (R,R)-configuration both at the C-3 position and the phosphorusatom was found to be potently active, while the other diastereomeric isomers were almostinactive. A number of (R,R)-compounds synthesized here exhibited broad spectrum activitieswith nanomolar Ki values against MMP-1, -3, -9, and TACE and also showed nanomolar IC50values against HB-EGF shedding in a cell-based inhibition assay. The modeling study usingX-ray structure of MMP-3 suggested the possible binding mode of the phosphonamide-basedinhibitors.
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