The synthesis and biological evaluation of non-peptidic matrix metalloproteinase inhibitors

Martin, Fionna M.; Beckett, R.Paul; Bellamy, Claire L.; Courtney, Paul; Davies, Stephen J.; Drummond, Alan H.; Dodd, Rory; Pratt, Lisa M.; Patel, Sanjay R.; Ricketts, Michelle L.; Todd, Richard S.; Tuffnell, Andrew R.; Ward, John W.S.; Whittaker, Mark

doi:10.1016/s0960-894x(99)00494-1

Cited by 23 publications

(6 citation statements)

References 14 publications

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“…Although a substantial number of nonpeptide sulfonamide hydroxamate MMPIs have been studied, almost all of these compounds (such as CGS-27023A) [37] have been derived fromamino acids, with a single carbon linking the sulfonamide nitrogen and the zinc chelating hydroxamic acid moiety [38,39]. Rencently, Levin et al were interested in ascertaining whether novel, potent MMPIs 2 [40] ( Table 1) could be made by using an aromatic ring as the linker between the sulfonamide nitrogen and the hydroxamate.…”

Section: Hydroxamic Acid-based Mmp-13 Inhibitorsmentioning

confidence: 99%

New Hope for the Treatment of Osteoarthritis Through Selective Inhibition of MMP-13

Shi²,

Tang³

et al. 2011

CMC

115

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Osteoarthritis (OA) is the leading cause of joint pain and disability in middle-aged and elderly patients, and is characterized by progressive loss of articular cartilage that eventually leads to a complex process involving degradation of various components of the cartilage matrix, chief among them are the cartilage-specific type II collagen (CII) and aggrecan. While the loss of aggrecan is thought to be an early and reversible process, degradation of CII is considered to be irreversible and a key step in the loss of structural and functional integrity of cartilage. Among the various matrix metalloproteinases (MMPs), MMP-13 is specifically expressed in the cartilage of human OA patients and is not present in normal adult cartilage. It is the major collagenase in OA cartilage and has the highest activity against CII. However, the clinical utility of broad-spectrum MMP inhibitors developed for treatment of OA has been restricted by dose- and duration-dependent musculoskeletal side effects in humans. Consequently, selectively inhibiting the MMP-13 would seem to be an attractive therapeutic objective. This review mainly focuses on selective MMP-13 inhibitors development in terms of OA since the late 90s, in terms of synthetic compounds of low molecular mass incorporating specific zinc-binding groups, non-zinc-binding groups. In addition, dual inhibitors of MMP-13 and aggrecanase are also reviewed. Special emphasis is placed on logistic concerns for lead compound search as well as the structure-activity relationship (SAR) in this field. Through these methods, new hope is emerging for the treatment of OA through selective inhibition of MMP-13.

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Section: Hydroxamic Acid-based Mmp-13 Inhibitorsmentioning

confidence: 99%

New Hope for the Treatment of Osteoarthritis Through Selective Inhibition of MMP-13

Shi²,

Tang³

et al. 2011

CMC

115

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“…Novel succinyl peptidomimetic hydroxamates that contain sulfonamides at the P 1´-α position were prepared [127]. Depending upon the nature of the sulfonamide, either broad-spectrum MMP inhibitors or inhibitors selective for collagenase-1 and -3 could be realized.…”

Section: Succinate Peptidomimetic Inhibitors Of Mmpsmentioning

confidence: 99%

The Design, Structure, and Therapeutic Application of Matrix Metalloproteinase Inhibitors

Skiles¹,

Gonnella²,

Jeng³

2001

CMC

211

144

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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.

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“…The role of one of these, the matrix metalloproteinases (MMPs), in tumor progression and metastasis has been extensively investigated (Vihinen et al, 2005). MMPs are a family of zincdependent enzymes that degrade the major components of extracellular matrix (Martin et al, 1999) and affect tumor growth, invasion and metastasis (Bode and Maskos, 2003;Chakraborti et al, 2003;Rundhaug, 2005). MMPs have been correlated with cancer prognosis clinically and histopathologically (Leeman et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

MMP-9 from sublethally irradiated tumor promotes Lewis lung carcinoma cell invasiveness and pulmonary metastasis

et al. 2011

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Matrix metalloproteinases (MMPs) associate with tumor progression and metastasis. We sought to investigate the role of MMP-9 from sublethally irradiated tumor in accelerated pulmonary metastasis of Lewis lung carcinoma (LLC-LM) and the corresponding anti-metastasis strategies in C57BL/6 mice. We used Matrigel-coated Boyden chamber assays and chicken chorioallantoic membrane assays to evaluate the invasion capability of irradiated LLC-LM cells (7.5 Gy), reverse transcriptionpolymerase chain reaction and the western blot assay to investigate the expression of MMPs by irradiated cells, and small interfering RNA duplexes to inhibit MMP-9 expression. LLC-LM cells differing in MMP-2 or -9 expression were subcutaneously injected into right thighs and the resulting tumors were irradiated (10 Gy Â 5) to induce pulmonary metastasis. Radiation significantly enhanced MMP-9 at both the transcriptional and translational levels. MMP-9 siRNA significantly inhibited in vitro radiation-enhanced invasiveness. The number of radiation-accelerated pulmonary metastases was significantly reduced by MMP-9 knockdown and MMP-2/9 knockdown. Reverse transcription-polymerase chain reaction of LLC-LM cells in the blood and lung tissue revealed MMP-9 involvement in radiation-enhanced intravasation. Either higher-dose irradiation (30 Gy Â 2) or pretreatment with prototypical MMP-9 inhibitor, zoledronic acid, significantly reduced the number of pulmonary metastases. The viability of irradiated tumor was seen on both positron emission tomography and magnetic resonance imaging, and tumor/serum MMP-9 levels suggested the association of local control of primary tumor and inhibition of timedependent MMP-9 activities. Our results demonstrate that MMP-9 is crucially involved in radiation-enhanced LLC-LM cell invasiveness in vitro and in pulmonary metastasis from inadequately irradiated primary tumor in vivo.

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The synthesis and biological evaluation of non-peptidic matrix metalloproteinase inhibitors

Cited by 23 publications

References 14 publications

New Hope for the Treatment of Osteoarthritis Through Selective Inhibition of MMP-13

New Hope for the Treatment of Osteoarthritis Through Selective Inhibition of MMP-13

The Design, Structure, and Therapeutic Application of Matrix Metalloproteinase Inhibitors

MMP-9 from sublethally irradiated tumor promotes Lewis lung carcinoma cell invasiveness and pulmonary metastasis

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