Design and synthesis of acidic dipeptide hydroxamate inhibitors of procollagen C-proteinase

Procollagen C-proteinase (PCP) Is essential. for the cleavage of procollage n to collagen in the extracellular matrix of animals and is, therefore, of major relevance to studies of ectopic deposition of collagen during fibrosi s. In this study, we describe the design and synthesis of acidic side chain hydroxamate dipeptide inhibitors of PCP having IC50 values in the range 0. 1-10 mu M that mimic the location of aspartic acid residues in the P1' and P2' positions (i.e. immediately C-terminal) of the PCP cleavage site in pro collagen. Assays of PCP using purified human type I procollagen (a natural substrate of PCP) showed that the structure activity relationship of the in hibitors was improved with a glutamic acid mimic at the P1' position. The r esults also showed that the presence of an acidic side chain at the P2' pos ition was not necessary for PCP inhibition. Marimastat and BB3103, which ar e highly effective inhibitors of matrix metalloproteinases and ADAMS protei nases, respectively, did not inhibit PCP. Copyright (C) 2000 European Pepti de Society and John Wiley & Sons, Ltd.