Preface [Hot Topic: Matrix Metalloproteinase Inhibitors (Guest Editor: Jeremy I. Levin)]

The matrix metalloproteinases (MMPs) are a family of more than 20 zinc-dependent mammalian enzymes, both membrane bound and secreted, most of which are involved in the cleavage of some component of the extracellular matrix (ECM), including collagen and gelatin. Related enzyme families include the adamalysins (ADAMs) and the ADAM-TS enzymes. The discovery of these important enzymes and their physiological functions began in the 1960s and still continues 40 years later. Furthermore, the apparent importance of the MMPs and ADAMs in the etiology of several debilitating diseases for which only palliative treatments had been available has made them exceedingly attractive targets for drug discovery programs at virtually every major pharmaceutical company and many academic institutions. From the 1990s to the present an explosion of patent applications and publications has delivered potent inhibitors of MMPs, TACE, and aggrecanases evolving from peptidic scaffolds bearing a variety of zinc chelators to non-peptides, some even devoid of any zinc ligating moiety. Unfortunately, clinical trials of MMP and TACE inhibitors have so far failed to deliver on the great promise envisioned for this class of molecules. Drug candidates in oncology, osteoarthritis and rheumatoid arthritis have almost uniformly failed to provide efficacy, or an acceptable risk-benefit profile, for advancing past Phase III clinical studies. In this context research into inhibitors of MMPs and ADAMs awaits advances to determine the best enzyme targets for particular therapeutic areas, and the degree of subtype specificity required of these inhibitors to allow their safe use as chronically administered drugs. In this issue are presented several different approaches to the design and synthesis of MMP and TACE inhibitors. In the first review, by Wada, the progression from peptidic hydroxamate, broad spectrum MMP inhibitors to more selective non-peptide, reverse hydroxamate inhibitors of gelatinases is described. This program resulted in a clinical candidate in oncology. In the second review, Hanessian and Moitessier present their elegant combination of structure-based design and organic synthesis in exploring potent and selective sulfonamide hydroxamate inhibitors. The third review, by Levin, describes the MMP / TACE activity of aryl hydroxamic acids. These scaffolds run the gamut from broad spectrum inhibitors, to more selective inhibitors of MMP-9 and MMP-13 with no TACE activity, to potent MMP / TACE inhibitors. In the fourth review, Rush and Powers report on the application and importance of structural information accumulated from X-ray, NMR and molecular modeling to guide the design of potent and diverse inhibitors. Finally, I would like to offer my thanks to all the authors who took the time and made the effort to contribute to this issue.