Matrix Metalloproteinase Inhibitors: Current Status

Abstract

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.

Matrix Metalloproteinase Inhibitors: A Structure−Activity Study

“…Finally, the incorporation of doubly substituted amides at the inhibitor terminus (compounds 6x − z , aa ) caused a drop in potency. This result is consistent with the importance of an additional hydrogen bond between the terminal amide proton and the enzyme active sites …”

“…Comparable results were noted with compound 6ccc , the methylated version of compound 6w . These data, shown in Table , support the importance of the hydrogen bonding interaction present between the internal amide proton and the enzyme backbone. , …”

“…Shown in Figure is a representation of the fibroblast collagenase binding site with a bound inhibitor. The interactions shown are predicted from published X-ray data involving fibroblast collagenase and a related inhibitor . Comparisons of available crystallographic information indicate significant sequence and structure homology from one MMP to the next.…”

Molecular Recognition of Protein−Ligand Complexes: Applications to Drug Design

“…Despite the rarity of LHS inhibitors, crystallographic information is available for one such inhibitor, Pro-Leu-Gly-NHOH, and it shall be briefly discussed near the end of this section. Several reviews of MMP inhibitors have appeared recently which cover SAR trends in detail, ,− but the structural basis for inhibition has not been previously reviewed.

…”

High-Resolution Solution Structure of the Inhibitor-Free Catalytic Fragment of Human Fibroblast Collagenase Determined by Multidimensional NMR

“…The matrix metalloproteinase (MMP) family, which includes the collagenases, stromelysins, and gelatinases, is involved in the degradation of the extracellular matrix which is associated with normal tissue remodeling processes such as pregnancy, wound healing, and angiogenesis ( − ). These enzymes are modular with both propeptide and catalytic domains being common to the entire family ( , ) while requiring both zinc and calcium for catalytic activity ( − ).…”