Design Of Matrix Metalloproteinases Inhibitors Research Articles

Phosphonate Emerging Zinc Binding Group in Matrix Metalloproteinase Inhibitors.

Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases, capable to degrade the extracellular matrix (ECM) in physiologic conditions. Because of their overexpression and pivotal role in many pathological events, they have been proposed as a therapeutic and prognostic target for a number of diseases. Selectivity among MMPs is essential for realizing the clinical potential of inhibitors. The design of MMP inhibitors (MMPIs) has largely focused on development of various compounds containing a zinc binding group (ZBG) in their structure, with hydroxamate being the most potent one. Due to the high degree of homology in the catalytic domain of all the MMPs, the specificity and selectivity of first generation hydroxamate MMPIs were minimal, with several off-target effects and binding to other metzincins. This review highlights the role of phosphonate as ZBG in the design and development of new MMPIs.

The application of x-ray, NMR, and molecular modeling in the design of MMP inhibitors.

The following review discusses the successful application of X-ray, NMR, and molecular modeling in the design of potent and selective inhibitors of matrix metalloproteinases (MMPs) and TNFalpha-converting enzyme (TACE) from Wyeth. The importance of protein and ligand mobility as it impacts structure-based design is also discussed. The MMPs are an active target for a variety of diseases, including cancer and arthritis.

The design, structure, and therapeutic application of matrix metalloproteinase inhibitors.

Matrix metalloproteinases (MMPs) are a family of zinc-containing enzymes involved in the degradation and remodeling of extracellular matrix proteins. The activities of these enzymes are well regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs). Chronic stimulation of MMP activities due to an imbalance in the levels of MMPs and TIMPs has been implicated in the pathogenesis of a variety of diseases such as cancer, osteoarthritis, and rheumatoid arthritis. Thus, MMP inhibitors are expected to be useful for the treatment of these disorders. This article reviews briefly the biochemistry of MMPs and evidence for their pathogenic roles using molecular biology approaches. Biomolecular structures used in the design of MMP inhibitors are thoroughly covered. Major emphasis is on recently published potent, small molecular weight MMP inhibitors and their pharmacological properties. Finally, available clinical results of compounds in development are summarized.

Design and synthetic considerations of matrix metalloproteinase inhibitors.

Experimental evidence confirms that the matrix metalloproteinases (MMPs) play a fundamental role in a wide variety of pathologic conditions that involve connective tissue destruction including osteoarthritis and rheumatoid arthritis, tumor metastasis and angiogenesis, corneal ulceration, multiple sclerosis, periodontal disease, and atherosclerosis. Modulation of MMP regulation is possible at several biochemical sites, but direct inhibition of enzyme action provides a particularly attractive target for therapeutic intervention. Hypotheses concerning inhibition of specific MMP(s) with respect to disease target and/or side-effect profile have emerged. Examples are presented of recent advances in medicinal chemistry approaches to the design of matrix metalloproteinase inhibitors (MMPIs), approaches that address structural requirements and that influence potency, selectivity, and bioavailability. Two important approaches to the design, synthesis, and biological evaluation of MMPIs are highlighted: (1) the invention of alternatives to hydroxamic acid zinc chelators and (2) the construction of nonpeptide scaffolds. One current example in each of these two approaches from our own work is described.

Human matrix metalloproteinase specificity studies using collagen sequence-based synthetic peptides.

The matrix metalloproteinase (MMP)/matrixin family has been implicated in both normal tissue remodeling and a variety of diseases associated with abnormal turnover of extracellular matrix components. To better understand MMP behaviors and to aid in the design of MMP inhibitors, a variety of sequence specificity studies have been performed using collagen sequence-based peptides and MMP family members. Results of these studies have been valuable for defining the differences in MMPs and for creating fluorogenic substrates that can continuously monitor MMP activity. However, these studies have also demonstrated that these peptides may not be very good models of native MMP substrates, and that the additivity principle is not always applicable for designing synthetic MMP substrates.

Solution structures of stromelysin complexed to thiadiazole inhibitors.

Unregulated or overexpressed matrix metalloproteinases (MMPs), including stromelysin, collagenase, and gelatinase. have been implicated in several pathological conditions including arthritis and cancer. Small-molecule MMP inhibitors may have therapeutic value in the treatment of these diseases. In this regard, the solution structures of two stromelysin/ inhibitor complexes have been investigated using 1H, 13C, and 15N NMR spectroscopy. Both-inhibitors are members of a novel class of matrix metalloproteinase inhibitor that contain a thiadiazole group and that interact with stromelysin in a manner distinct from other classes of inhibitors. The inhibitors coordinate the catalytic zinc atom through their exocyclic sulfur atom, with the remainder of the ligand extending into the S1-S3 side of the active site. The binding of inhibitor containing a protonated or fluorinated aromatic ring was investigated using 1H and 19F NMR spectroscopy. The fluorinated ring was found to have a reduced ring-flip rate compared to the protonated version. A strong, coplanar interaction between the fluorinated ring of the inhibitor and the aromatic ring of Tyr155 is proposed to account for the reduced ring-flip rate and for the increase in binding affinity observed for the fluorinated inhibitor compared to the protonated inhibitor. Binding interactions observed for the thiadiazole class of ligands have implications for the design of matrix metalloproteinase inhibitors.

Inhibition of Matrix Metalloproteinases: Structure Based Design

Matrix metalloproteinases (MMP) have been implicated in a variety of diseases in which the destruction of connective tissue is an important pathological event. These include osteo and rheumatoid arthritis, tumor metastasis and angiogenesis, and corneal ulceration. As a result, there has been a great deal of activity directed towards the design of MMP inhibitors as therapeutic agents for the treatment of these conditions. Progress in the field has now evolved to a degree where potent, low molecular weight, orally active inhibitors have been discovered and advanced to clinical trials. While a majority of inhibitors are dipeptide derivatives, a non-peptide, orally active inhibitor has recently been reported. Some success has also been achieved in the design of subtype selective MMP inhibitors. The elucidation of X-ray and 0NMR structures of several MMPs, and the ability to create homology models of others has provided an understanding of some of the structural requirements leading to potency and specificity. Herein is a review of recent advances in the biology and chemistry of MMPs and MMP inhibitors, including the association of MMPs with specific disease processes, structure activity relationships of MMP inhibitors and factors affecting enzyme specificity and their correlation with MMP structure.

Human matrix metalloproteinase specificity studies using collagen sequence-based synthetic peptides

The matrix metalloproteinase (MMP)/matrixin family has been implicated in both normal tissue remodeling and a variety of diseases associated with abnormal turnover of extracellular matrix components. To better understand MMP behaviors and to aid in the design of MMP inhibitors, a variety of sequence specificity studies have been performed using collagen sequence-based peptides and MMP family members. Results of these studies have been valuable for defining the differences in MMPs and for creating fluorogenic substrates that can continuously monitor MMP activity. However, these studies have also demonstrated that these peptides may not be very good models of native MMP substrates, and that the additivity principle is not always applicable for designing synthetic MMP substrates.

Inhibition of matrix metalloproteinases by hydroxamates containing heteroatom-based modifications of the P1' group.

In this study, structure-based drug design of matrix metalloproteinase inhibitors [human fibroblast collagenase (HFC), human fibroblast stromelysin (HFS), and human neutrophil collagenase (HNC)] was utilized in the development of potent hydroxamates which contain novel, heteroatom-based modifications of the P1' group. A series containing a P1' butyramide group resulted in a nanomolar potent and selective HNC inhibitor as well as a dual HFS/HNC inhibitor. Benzylic ethers with a four- or five-carbon methylene linker in the P1' position also produced nanomolar potent HFS/HNC inhibition and micromolar potent HFC inhibition as expected. Surprisingly, the phenolic ethers of the same overall length as the benzylic ethers showed nanomolar potencies against HFC, as well as HFS and HNC. The potency profile of the phenolic ethers was optimized by structure-activity relationships of the phenolic group and the C-terminal amide. These inhibitors may help elucidate the in vivo roles of matrix metalloproteinases in normal and disease states.