Design, Synthesis, and Evaluation of a Mechanism-Based Inhibitor for Gelatinase A

Ikejiri, Masahiro; Bernardo, M. Margarida; Meroueh, Samy O.; Brown, Stephen H.M.; Chang, Mayland; Fridman, Rafael; Mobashery, Shahriar

doi:10.1021/jo050339+

Cited by 43 publications

(44 citation statements)

References 11 publications

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“…Due to the fact that MMPs play a prominent role in tissue remodeling processes, a large effort was put in place to develop pharmacological MMP inhibitors (83,93,99,172,267,319,320,332,354,357,363,445,528). The development efforts were not targeted toward myocardial remodeling per se, but rather for indications in cancer and rheumatologic/inflammatory disorders.…”

Section: Myocardial Matrix Metalloproteinases: Lessons From Pharmmentioning

confidence: 99%

“…This selective MMP inhibitor was evaluated in several animal models of myocardial remodeling and eventually advanced to a clinical study. These pharmacological developments and studies are likely to be considered the first iteration of selective MMP inhibitors, as compounds with a much more restricted inhibitor profile are under development (83,93,99,172,357). Finally, it must be recognized that therapeutic interventions such as agents that inhibit neurohormonal activity or mechanical stimuli would likely in turn modify MMP expression/activity (31,171,193,211,227,338,344,376,380,425).…”

Section: Myocardial Matrix Metalloproteinases: Lessons From Pharmmentioning

confidence: 99%

“…Nevertheless, since the MMP system clearly causes cardiovascular remodeling, then alternative pharmacological approaches such as using doxycycline as an MMP inhibitor remain in clinical evaluation (47). In addition, MMP inhibitors with a highly specific inhibitory profile continue to be developed and refined (83,93,99,172,357).…”

Section: Clinical Studies Of Mmp Inhibitionmentioning

confidence: 99%

See 2 more Smart Citations

Myocardial Matrix Remodeling and the Matrix Metalloproteinases: Influence on Cardiac Form and Function

Spinale¹

2007

Physiological Reviews

1,008

1,023

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It is now becoming apparent that dynamic changes occur within the interstitium that directly contribute to adverse myocardial remodeling following myocardial infarction (MI), with hypertensive heart disease and with intrinsic myocardial disease such as cardiomyopathy. Furthermore, a family of matrix proteases, the matrix metalloproteinases (MMPs) and the tissue inhibitors of MMPs (TIMPs), has been recognized to play an important role in matrix remodeling in these cardiac disease states. The purpose of this review is fivefold: 1) to examine and redefine the myocardial matrix as a critical and dynamic entity with respect to the remodeling process encountered with MI, hypertension, or cardiomyopathic disease; 2) present the remarkable progress that has been made with respect to MMP/TIMP biology and how it relates to myocardial matrix remodeling; 3) to evaluate critical translational/clinical studies that have provided a cause-effect relationship between alterations in MMP/TIMP regulation and myocardial matrix remodeling; 4) to provide a critical review and analysis of current diagnostic, prognostic, and pharmacological approaches that utilized our basic understanding of MMP/TIMPs in the context of cardiac disease; and 5) most importantly, to dispel the historical belief that the myocardial matrix is a passive structure and supplant this belief that the regulation of matrix protease pathways such as the MMPs and TIMPs will likely yield a new avenue of diagnostic and therapeutic strategies for myocardial remodeling and the progression to heart failure.

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Section: Myocardial Matrix Metalloproteinases: Lessons From Pharmmentioning

confidence: 99%

Section: Myocardial Matrix Metalloproteinases: Lessons From Pharmmentioning

confidence: 99%

Section: Clinical Studies Of Mmp Inhibitionmentioning

confidence: 99%

See 1 more Smart Citation

Myocardial Matrix Remodeling and the Matrix Metalloproteinases: Influence on Cardiac Form and Function

Spinale¹

2007

Physiological Reviews

1,008

1,023

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“…Recently, the design of the prototypic inhibitor was modified and a new generation of mechanism-based MMP2-specific MMPIs were developed (Ikejiri et al, 2005). So, although pharmaceutical companies would prefer to develop noncovalent inhibitors, for short or medium duration patient dosing or in very serious cancers, the risk of side effects may be acceptably low to consider the use of this class of compound.…”

Section: Covalent Inhibitorsmentioning

confidence: 99%

Towards third generation matrix metalloproteinase inhibitors for cancer therapy

2006

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The failure of matrix metalloproteinase (MMP) inhibitor drug clinical trials in cancer was partly due to the inadvertent inhibition of MMP antitargets that counterbalanced the benefits of MMP target inhibition. We explore how MMP inhibitor drugs might be developed to achieve potent selectivity for validated MMP targets yet therapeutically spare MMP antitargets that are critical in host protection.

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“…A recent breakthrough in this field was achieved by identifying the first highly selective synthetic inhibitor of MMP-13 (21). Selective inhibitors for MMP-2 and MMP-9 have also been reported recently, but their degree of selectivity toward MMPs is less than that achieved for the MMP-13-selective inhibitor (22).…”

mentioning

confidence: 99%

Development of Selective Inhibitors and Substrate of Matrix Metalloproteinase-12

Devel

Rogakos

David

et al. 2006

Journal of Biological Chemistry

141

154

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The matrix metalloproteinases (MMPs)2 form a group of structurally related extracellular zinc endoproteases able to degrade at least one protein component of the extracellular matrix (1). Based on this property, MMPs are considered to be critical mediators of both normal and pathological tissue remodeling processes (2, 3). Their overexpression is observed in and associated with a variety of diseases, including cancer (4, 5), arthritis (6), multiple sclerosis (7,8), and atherosclerosis (9, 10). Therefore, there is substantial interest in developing MMP synthetic inhibitors for a variety of therapeutic indications (11)(12)(13)(14)(15). Results of the first clinical trials with broad spectrum MMP inhibitors in cancer therapy were disappointing, highlighting the need for better understanding of the exact role of each MMP during the different stages of tumor progression (16). Recent research in this field has focused on the development of inhibitors that fully differentiate one MMP from another (17). This is a particularly difficult task, since the topology and nature of the residues in the enzyme's active site are highly conserved among the different MMPs (18). Moreover, parts of the MMP catalytic domain, which play a critical role in enzyme specificity, seem to be highly flexible (19,20). This situation may explain why most previously reported MMP synthetic inhibitors preferentially inhibit some MMPs but are not exclusive inhibitors of a single MMP. A recent breakthrough in this field was achieved by identifying the first highly selective synthetic inhibitor of MMP-13 (21). Selective inhibitors for MMP-2 and MMP-9 have also been reported recently, but their degree of selectivity toward MMPs is less than that achieved for the MMP-13-selective inhibitor (22).To identify highly selective MMP inhibitors, libraries of phosphinic peptides were prepared. Phosphinic peptides are good transition state mimics and have been shown to behave as highly potent inhibitors of different zinc metalloproteinases (23). To probe the SЈ 1 cavity of MMPs, a chemical strategy that makes it possible to prepare phosphinic peptides harboring various substituents in their PЈ 1 position was used (see Scheme 1). This strategy relies on the use of a common precursor, which can be modified in one step, to prepare phosphinic peptides displaying substituted isoxazole side chains in their PЈ 1 position (24). In such phosphinic peptides, the isoxazole ring is used as a rigid scaffold to project in the right orientation various chemical groups able to interact with the SЈ 1 subsite of MMPs, which corresponds to a deep cavity. Based on this strategy, four libraries of phosphinic peptides, containing four different isoxazole side chains in their PЈ 1 position, were prepared by introducing additional chemical diversity in the PЈ 2 and PЈ 3 positions of the inhibitors (see Scheme 1). Screening of these libraries against 10 different MMPs allowed us to identify highly selective inhibitors of MMP-12. Based on the unique structure of these inhibitors, a highl...

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Design, Synthesis, and Evaluation of a Mechanism-Based Inhibitor for Gelatinase A

Cited by 43 publications

References 11 publications

Myocardial Matrix Remodeling and the Matrix Metalloproteinases: Influence on Cardiac Form and Function

Myocardial Matrix Remodeling and the Matrix Metalloproteinases: Influence on Cardiac Form and Function

Towards third generation matrix metalloproteinase inhibitors for cancer therapy

Development of Selective Inhibitors and Substrate of Matrix Metalloproteinase-12

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