Phosphinic pseudo-tripeptides as potent inhibitors of matrix metalloproteinases: A structure-activity study

Several phosphinic pseudo-tripeptides of general formula R-Xaa Psi (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 meta lloproteinase, collagenases 1 and 2, and matrilysin. With the exception of collagenase-1 and matrilysin, phosphinic pseudo-tripeptides behave as highl y potent inhibitors of matrix metalloproteinases, provided they contain in P-1' position an unusual long aryl-alkyl substituent. Study of structure-ac tivity relationships regarding the influence of the R and Xaa' substituents in this series may contribute to the design of inhibitors able to block on ly a few members of the matrix metalloproteinase family.