A new development of matrix metalloproteinase inhibitors: twin hydroxamic acids as potent inhibitors of MMPs

Rossello, Armando; Nuti, Elisa; Catalani, Maria Pia; Carelli, Paolo; Orlandini, Elisabetta; Rapposelli, Simona; Tuccinardi, Tiziano; Atkinson, Susan J.; Murphy, Gillian; Balsamo, Aldo

doi:10.1016/j.bmcl.2005.03.002

Cited by 23 publications

(22 citation statements)

References 31 publications

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“…100 Also, the carboxylic acid scaffold of those MMP inhibitors was used to develop selective MMP-12 inhibitors for treatment of chronic obstructive pulmonary disease, 101 Selective hydroxamic acid inhibitors of MMP-2 have been developed as potent anti-angiogenic agents, and inhibitor 7 is the most selective MMP-2 inhibitor of this series. 86 Another hydroxamate MMP inhibitor with specificity towards MMP-3 was designed for treatment of chronic non-healing wounds. 88 Other ZBGs have been developed to improve selectivity, bioavailability, and pharmacokinetics, and include oxygen, nitrogen, and sulfur donor–atom ligands and monodentate, bidentate, and tridentate chelators.…”

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

120

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

120

161

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“…A contributing factor to the effectiveness of hydroxamates is the hydrogen bonding that results between the heteroatoms of the ZBG and neighboring amino acid residues that are conserved in all MMP active sites. Several hydroxamate- and carboxylate-based MMPIs show good selectivity among different MMPs (Cherney et al, 2004; Rossello et al, 2005; Nakatani et al, 2006; Whitlock et al, 2007; Subramaniam et al, 2008). Although hydroxamate MMPIs are potent inhibitors, many of them have shown adverse musculoskeletal side effects and poor oral bioavailability (Vihinen et al, 2005; Fingleton, 2008).…”

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

134

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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“…Detailed studies on these hydroxamates led to develop many potent MMP inhibitors, e.g., in a series of N-O-isopropyl sulfonamide-based hydroxamates studied by Nuti et el. [43], compound 12 was reported to be a very promising MMP-13 inhibitor. Similarly, in the study on sulfone N-formylhydroxyl amines, Wada et al [47] reported compounds 17e, f, g and h as the most selective for the inhibition of MMP-2 and MMP-9 over MMP-1 and out of these compounds 17f and 17h produced their effect at subnanomolar values of IC 50 against these two enzymes.…”

Section: Discussionmentioning

confidence: 99%

“…In a next communication, Rossello et al [43] reported some twin hydroxamic acids, such as (R,R)-29a,b, using some suitable linkers as 'a' and 'b'. Among them, the activities of only 3 compounds, 30-32, were reported against MMP-1, 2, 9 and 14.…”

Section: Recent Developmentmentioning

confidence: 97%

“…Nakatani et al [46] studied a series of N-benzoyl 4-aminobutyric acid hydroxamate analogs (39)(40)(41)(42)(43)(44) as matrix metalloproteinase inhibitors. These authors focused their attention on the chemical modification of the 4-aminobutyric acid part, using easily available starting materials, such as 4-aminobutyric acid, (+) -and (-)-malic acids, and D-and L-glutamic acid derivatives.…”

Section: Recent Developmentmentioning

confidence: 99%

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Recent Advances in Studies on Hydroxamates as Matrix Metalloproteinase Inhibitors: A Review

Yadav¹,

Gupta²,

Sharma³

et al. 2011

CMC

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Matrix metalloproteinases (MMPs) are a large family of calcium-dependent zinc- containing endopeptidases, which are responsible for the tissue remodeling and degradation of the extracellular matrix (ECM), including collagens, elastins, gelatin, matrix glycoproteins, and proteoglycan. The inappropriate expression of these MMPs constitutes part of the pathogenic mechanism in several diseases, therefore they are subject to inhibition. They can be inhibited by endogenous proteinase inhibitors such as 2-macroglobulin or by the family of tissue inhibitors of metalloproteinases (TIMPs), which are glycoproteins of molecular weight 21-30 kDa, consisting of 184-194 amino acid residues. Recently, many different classes of synthetic inhibitors have been developed in which the hydroxamic acidbased class of compounds (hydroxamates) have been most widely studied, as their hydroxamic acid group (CONHOH) enables them to act as a bidentate ligand with the zinc ion present in MMPs, leading to much stronger interaction with the receptor as compared to any other class of inhibitors. The present review describes in detail the recent development on this class of MMP inihibitors. Compounds like 12,17e, f, g and h, 45j, 45k, 50f, 62a, 63a, and 63b have been reported to be highly promising for further development.

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A new development of matrix metalloproteinase inhibitors: twin hydroxamic acids as potent inhibitors of MMPs

Cited by 23 publications

References 31 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

Recent Advances in Studies on Hydroxamates as Matrix Metalloproteinase Inhibitors: A Review

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