Phosphinic Pseudo-Tripeptides as Potent Inhibitors of Matrix Metalloproteinases:  A Structure−Activity Study

Several phosphinic pseudo-tripeptides of general formula R-XaaΨ(PO2-CH2)Xaa‘-Yaa‘-NH2 were synthesized and evaluated for their in vitro activities to inhibit stromelysin-3, gelatinases A and B, membrane type-1 matrix metalloproteinase, collagenases 1 and 2, and matrilysin. With the exception of collagenase-1 and matrilysin, phosphinic pseudo-tripeptides behave as highly potent inhibitors of matrix metalloproteinases, provided they contain in P1‘ position an unusual long aryl−alkyl substituent. Study of structure−activity relationships regarding the influence of the R and Xaa‘ substituents in this series may contribute to the design of inhibitors able to block only a few members of the matrix metalloproteinase family.