1-Hydroxy-2-pyridinone-based MMP inhibitors: Synthesis and biological evaluation for the treatment of ischemic stroke

Zhang, Yuemei; Fan, Xiaodong; Chakaravarty, Devraj; Xiang, Bangping; Scannevin, Robert H.; Huang, Zhihong; Ma, Jiechao; Burke, Sharon L.; Karnachi, Prabha; Rhodes, Kenneth J.; Jackson, Paul F.

doi:10.1016/j.bmcl.2007.10.045

Cited by 37 publications

(20 citation statements)

References 18 publications

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“…Compound 27 has a 47 hour half-life when administered intravenously at 2 mg/kg in rats, and has been shown to reduce brain edema in a mouse model of cerebral ischemia/reperfusion injury produced by transient occlusion of mid-cerebral artery. 116 …”

Section: Synthetic Mmp Inhibitorsmentioning

confidence: 99%

Matrix Metalloproteinase Inhibitors as Investigational and Therapeutic Tools in Unrestrained Tissue Remodeling and Pathological Disorders

Liu

Khalil

2017

Progress in Molecular Biology and Translational Science

118

161

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Matrix metalloproteinases (MMPs) are zinc-dependent proteolytic enzymes that degrade various proteins in the extracellular matrix (ECM). MMPs may also regulate the activity of membrane receptors and post-receptor signaling mechanisms, and thereby affect cell function. The MMP family includes collagenases, gelatinases, stromelysins, matrilysins, membrane-type MMPs and other MMPs. Inactive proMMPs are cleaved by other MMPs or proteases into active MMPs, which interact with various protein substrates in ECM and cell surface. MMPs regulate important biological processes such as vascular remodeling and angiogenesis, and may be involved in the pathogenesis of cardiovascular disorders such as hypertension, atherosclerosis, and aneurysm. The role of MMPs is often assessed by measuring their mRNA expression, protein levels, and proteolytic activity using gel zymography. MMP inhibitors are also used to assess the role of MMPs in different biological processes and pathological conditions. MMP activity is regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs), and the MMP/TIMP balance could determine the net MMP activity, ECM turnover, and tissue remodeling. Also, several synthetic MMP inhibitors have been developed. Synthetic MMP inhibitors include a large number of zinc binding globulins (ZBGs), in addition to non-ZBGs and mechanism-based inhibitors. MMP inhibitors have been proposed as potential tools in the management of osteoarthritis, cancer, and cardiovascular disorders. However, most MMP inhibitors have broad-spectrum actions on multiple MMPs and could cause undesirable musculoskeletal side effects. Currently, doxycycline is the only MMP inhibitor approved by the Food and Drug Administration. New generation biological and synthetic MMP inhibitors may show greater MMP specificity and fewer side-effects, and could be useful in targeting specific MMPs, reducing unrestrained tissue remodeling, and the management of MMP-related pathological disorders.

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Section: Synthetic Mmp Inhibitorsmentioning

confidence: 99%

Matrix Metalloproteinase Inhibitors as Investigational and Therapeutic Tools in Unrestrained Tissue Remodeling and Pathological Disorders

Liu

Khalil

2017

Progress in Molecular Biology and Translational Science

118

161

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“…Other ZBGs include 6-, 7-, and 8-membered heterocyclic chelators as 1-hydroxy-2-piperidinone, 1-hydroxyazepan-2-1, 1-hydroxyazocan-2-1, and 1-hydroxy-1,4-diazepan-2-1 (Zhang et al, 2008). Compound 27, which uses ZBG20, is selective to MMP-1 and moderately selective to MMP-3.…”

Section: Modulators Of Mmp Activitymentioning

confidence: 99%

Matrix Metalloproteinase Inhibitors as Investigative Tools in the Pathogenesis and Management of Vascular Disease

Benjamin

Khalil

2012

Experientia Supplementum

133

139

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Matrix metalloproteinases (MMPs) are proteolytic enzymes that degrade various components of the extracellular matrix (ECM). MMPs could also regulate the activity of several non-ECM bioactive substrates, and consequently affect different cellular functions. Members of the MMPs family include collagenases, gelatinases, stromelysins, matrilysins, membrane-type MMPs and others. Pro-MMPs are cleaved into active MMPs, which in turn act on various substrates in the ECM and on the cell surface. MMPs play an important role in the regulation of numerous physiological processes including vascular remodeling and angiogenesis. MMPs may also be involved in vascular diseases such as hypertension, atherosclerosis, aortic aneurysm, and varicose veins. MMPs also play a role in the hemodynamic and vascular changes associated with pregnancy and preeclampsia. The role of MMPs is commonly assessed by measuring their gene expression, protein amount, and proteolyic activity using gel zymography. Because there are no specific activators of MMPs, MMP inhibitors are often used to investigate the role of MMPs in different physiologic processes and in the pathogenesis of specific diseases. MMP inhibitors include endogenous tissue inhibitors (TIMPs) and pharmacological inhibitors such as zinc chelators, doxycycline and marimastat. MMP inhibitors have been evaluated as diagnostic and therapeutic tools in cancer, autoimmune and cardiovascular disease. Although several MMP inhibitors have been synthesized and tested both experimentally and clinically, only on MMP inhibitor, i.e. doxycycline, is currently approved by the Food and Drug Administration. This is mainly due to the undesirable side effects of MMP inhibitors especially on the musculoskeletal system. While most experimental and clinical trials of MMP inhibitors have not demonstrated significant benefits, some trials still showed promising results. With the advent of new genetic and pharmacological tools, disease-specific MMP inhibitors with fewer undesirable effects are being developed and could be useful in the management of vascular disease.

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“…[18,[29][30][31][32][33] These studies have identified new ZBGs, that are more potent than hydroxamic acids, some of which have been developed into potent, nonhydroxamate inhibitors of MMPs. [32,34,35] In the present study, a series of hydroxypyrone and hydroxypyridinone inhibitors have been synthesized and evaluated to demonstrate that the isoform selectivity of an MMPi can be influenced by the choice of ZBG. These observations are particularly notable, because the ZBGs employed in this study all use the same type and number of donor atoms (two oxygen atoms) to bind the Zn 2 + ion, and only possess subtle differences in electrostatics, hydrophobicity, and acidity.…”

Section: Introductionmentioning

confidence: 99%

Zinc‐Binding Groups Modulate Selective Inhibition of MMPs

et al. 2008

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The need for selective matrix metalloproteinase (MMP) inhibition is of interest because of the range of pathologies mediated by different MMP isoforms. The development of more selective MMP inhibitors (MMPi) may help to overcome some of the undesired side effects that have hindered the clinical success of these compounds. In an effort to devise new approaches to selective inhibitors, herein we describe several novel MMPi and show that their selectivity is dependent on the nature of the zinc-binding group (ZBG). This is in contrast to most current MMPi, which obtain isoform selectivity solely from the peptidomimetic backbone portion of the compound. In the present study, six different hydroxypyrone and hydroxypyridinone ZBGs were appended to a common biphenyl backbone and the inhibition efficiency of each inhibitor was determined in vitro (IC(50) values) against MMP-1, -2, -3, -7, -8, -9, -12, and -13. The results show that the selectivity profile of each inhibitor is different as a result of the various ZBGs. Computational modeling studies were used to explain some trends in the observed selectivity profiles. To assess the importance of the ZBG in a biological model, two of the semiselective, potent MMPi (and one control) were evaluated using an isolated perfused rat heart system. Hearts were subjected to ischemia reperfusion injury, and recovery of contractile function was examined. In this model, only one of the two MMPi showed significant and sustained heart recovery, demonstrating that the choice of ZBG can have a significant effect in a relevant pathophysiological endpoint.

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1-Hydroxy-2-pyridinone-based MMP inhibitors: Synthesis and biological evaluation for the treatment of ischemic stroke

Cited by 37 publications

References 18 publications

Matrix Metalloproteinase Inhibitors as Investigational and Therapeutic Tools in Unrestrained Tissue Remodeling and Pathological Disorders

Matrix Metalloproteinase Inhibitors as Investigational and Therapeutic Tools in Unrestrained Tissue Remodeling and Pathological Disorders

Matrix Metalloproteinase Inhibitors as Investigative Tools in the Pathogenesis and Management of Vascular Disease

Zinc‐Binding Groups Modulate Selective Inhibition of MMPs

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