The matrix metalloproteinase stromelysin-1 (MMP-3) is inhibited more strongly by peptidyl phosphinic acid 7 than by its corresponding phosphonamidate and phosphonate analogs. Extending a benzyl group at PI' to a phenylethyl group in 8 further increases the potency (Ki = 1.4 nM). Enhanced potency with an extended substituent into the P3 region was observed.
Matrix metalloproteinases (MMPs) have been implicated as causative agents in the degradation of articular cartilage in diseases such as rheumatoid and osteoarthritis and thus have been targets of intensive efforts to discover potent, selective inhibitors. 1-3 Given the discoordinate expression 4,5 and unknown activation process(es) of these enzymes, highly selective inhibitors of each MMP may help to define the role of these proteinases in both normal and pathological cartilage remodeling. To that end, we sought to develop selective inhibitors of stromelysin-1 (MMP-3), a proteoglycanase present in large amounts in arthritic joints. 6 Herein is described the preparation of phosphorus-containing dipeptides and their evaluation as inhibitors of several members of the MMP family.