J.R. Morphy*, T.A. Millican and J.R. Porter Pages 743 - 762 ( 20 )
Due to the increasing evidence for the involvement of the matrix metalloproteinases (MMPs) in a variety of tissue degenerative disorders, such as arthritis and cancer, there is considerable interest in designing agents which inhibit their action, either collectively or selectively. Historically, MMP inhibitors have been designed using knowledge of the substrate cleavage sites of the enzymes, early collagenase inhibitors bearing similarity to the cleavage site of type-1 collagen. This review will describe the recent design of specific inhibitors of stromelysin and gelatinase based upon their own substrate preferences. The structure of these inhibitors will be rationalised in terms of the recently published crystal structures of the MMPs. The development of a new generation of peptide-based, yet orally active, inhibitors will be reviewed and their progress towards the clinic assessed. Recent advances in the discovery of non-peptide MMP inhibitors will also be described.