Since the early 1980s, there has been considerable interest in the design of MMP inhibitors, but it is only recently that clinical evaluation of compounds of this class has commenced (42-47). A key structural feature of all potent MMP inhibitors is the presence of a chemical functional group that is capable of chelating the active site zinc(II) ion, which is a ubiquitous feature of the MMP enzymes. The first inhibitors to be identified were peptide derivatives designed on the basis of the sequence around the glycine-isoleucine and glycine-leucine at the site in the collagen a-chain, which is initially cleaved by collagenase (Fig. 2). In these pioneering studies, the zinc-binding group (ZBG) was incorporated into peptide analogs of the sequence on the left-hand side, right-hand side, or both sides of the cleavage site (Fig. 2). Other workers followed the serendipidous approach of screening compound libraries and/or natural products, and succeeded in identifying novel compounds and others that are structurally related to inhibitors obtained by substrate-based design. Although considerable insight into MMP ligand interactions has been obtained from the study of inhibitor structure-activity relation-
ships (SAR) (48), and elegant studies of enzyme substrate specificity (49-51), it is the recent advent of high-resolution X-ray (52-62) and NMR (63) structures of MMP-inhibitor complexes that has provided new paradigms for inhibitor design. To date, the new technology of combinatorial chemistry has had little impact on MMP-inhibitor design (64-67).
Medicinal chemists have been faced with the dilemma of whether to design broad-spectrum or selective inhibitors, and the difficulty of obtaining oral activity. In principle, selective inhibitors should provide greater specificity and, hence, safety than broad-spectrum MMP inhibitors. However, human and animal studies have revealed that a number of the MMP family members are often coexpressed in disease states, making it difficult to single out a particular MMP as being casual (43). Although it has proved possible to obtain satisfactory oral activity for selected pseudopeptide MMP inhibitors, it has generally been considered that acceptable pharmacokinetics can be more readily obtained for nonpeptidic compounds. Structures for the compounds discussed below in the text are shown in Figs. 3-6 and in vitro enzyme activities are given in Table 2.
(13) CGS 27023A
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