Anti-arthritic activity of hydroxamic acid-based pseudopeptide inhibitors of matrix metalloproteinases and TNFα processing

DiMartino, Michael J.; Wolff, Christine; High, Whitney A.; Stroup, George B.; Hoffman, Sandy J.; Laydon, Jeffrey T.; Lee, J. C.; Bertolini, Donald R.; Galloway, W A; Crimmin, M. J.; Davis, Martin J.; Davies, Stephen J.

doi:10.1007/s000110050175

Cited by 42 publications

(43 citation statements)

References 13 publications

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“…In this study, we have demonstrated the induction of MMP-9 in primary human mast cells by a proinflammatory cytokine (TNF-␣), a cytokine strongly linked to the pathogenesis of RA (45). The TNF-mediated up-regulation of MMP-9 was strongly abrogated by IFN-␥.…”

Section: Discussionmentioning

confidence: 87%

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Human Mast Cell-Derived Gelatinase B (Matrix Metalloproteinase-9) Is Regulated by Inflammatory Cytokines: Role in Cell Migration

Girolamo

Indoh

Jackson

et al. 2006

The Journal of Immunology

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Mast cells are key effectors in the pathogenesis of inflammatory and tissue destructive diseases such as rheumatoid arthritis (RA). These cells contain specialized secretory granules loaded with bioactive molecules including cytokines, growth factors, and proteases that are released upon activation. This study investigated the regulation of matrix metalloproteinase MMP-9 (gelatinase B) in human mast cells by cytokines that are known to be involved in the pathogenesis of RA. Immunohistochemical staining of synovial tissue showed abundant expression of MMP-9 by synovial tissue mast cells in patients with RA but not in normal controls. The expression, activity, and production of MMP-9 in mast cells was confirmed by RT-PCR, zymography, and Western blotting using cord blood-derived human mast cells (CB-HMC). Treatment of CB-HMC with TNF-α significantly increased the expression of MMP-9 mRNA and up-regulated the activity of MMP-9 in a time- and dose-dependent manner. By contrast, IFN-γ inhibited MMP-9 mRNA and protein expression. The cytokine-mediated regulation of MMP-9 was also apparent in the human mast cell line (HMC-1) and in mouse bone marrow-derived mast cells. Furthermore, TNF-α significantly increased the invasiveness of CB-HMC across Matrigel-coated membranes while the addition of IFN-γ, rTIMP-1, or pharmacological MMP inhibitors significantly reduced this process. These observations suggest that MMP-9 is not a stored product in mast cells but these cells are capable of producing this enzyme under inflammatory conditions that may facilitate the migration of mast cell progenitors to sites of inflammation and may also contribute to local tissue damage.

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Section: Discussionmentioning

confidence: 87%

“…TNF-␣ plays a key role in the pathogenesis of RA and is currently a therapeutic target in this and other inflammatory diseases (45). TNF-␣ positively regulates expression of MMPs that FIGURE 3.…”

Section: Cytokine Regulation Of Mast Cell-derived Mmp-9mentioning

confidence: 99%

Human Mast Cell-Derived Gelatinase B (Matrix Metalloproteinase-9) Is Regulated by Inflammatory Cytokines: Role in Cell Migration

Girolamo

Indoh

Jackson

et al. 2006

The Journal of Immunology

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“…Stimulation of TNF-␣ release from monocytes in human blood has been studied both in vivo and in vitro after LPS challenge (Mohler et al, 1994;DiMartino et al, 1997). The production of human TNF-␣ has been documented in vivo both clinically in sepsis patients and experimentally, after healthy volunteers received systemic LPS (Tracey et al, 1993;Dekkers et al, 1999).…”

Section: Ro 32-7315 An Orally Active Inhibitor Of Tumor Necrosis Facmentioning

confidence: 99%

“…The production of human TNF-␣ has been documented in vivo both clinically in sepsis patients and experimentally, after healthy volunteers received systemic LPS (Tracey et al, 1993;Dekkers et al, 1999). The majority of reported in vitro studies used primary cells in culture or tumor lines (Gearing et al, 1994;DiMartino et al, 1997). Although these systems have provided valuable information, they cannot take account of the complexities that can occur in whole blood such as protein binding, compartmentalization, and possible interactions between different cell types.…”

Section: Ro 32-7315 An Orally Active Inhibitor Of Tumor Necrosis Facmentioning

confidence: 99%

“…1) is among the first of a new generation of potent, hydroxamicacid-containing TACE inhibitors with greater selectivity over the MMP family of enzymes. In addition to the potency and selectivity of this compound, a marked improvement in the in vivo biological profile compared with compounds such as BB 1101 (DiMartino et al, 1997;Barlaam et al, 1999) was observed. In this report, we describe the in vitro and in vivo biological profile of Ro 32-7315, a selective inhibitor of TACE.…”

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confidence: 92%

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(E)-2(R)-[1(S)-(Hydroxycarbamoyl)-4-phenyl-3-butenyl]-2′-isobutyl-2′-(methanesulfonyl)-4-methylvalerohydrazide (Ro 32-7315), a Selective and Orally Active Inhibitor of Tumor Necrosis Factor-α Convertase

Beck

Bottomley²,

Bradshaw³

et al. 2002

J Pharmacol Exp Ther

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Tumor necrosis factor-␣ (TNF-␣), a cytokine secreted by inflammatory cells, has been implicated in several inflammatory disease, is a potent, orally active inhibitor of the TNF-␣ convertase (TACE), an enzyme responsible for proteolytic cleavage of the membrane bound precursor, pro-TNF-␣. Ro 32-7315 inhibited a recombinant form of TACE (IC 50 ϭ 5.2 nM) with selectivity over related matrix metalloproteinases. In a cellular assay system, THP-1 cell line, and in human and rat whole blood, Ro 32-7315 significantly reduced lipopolysaccharide (LPS)-induced TNF-␣ release with IC 50 values of 350 Ϯ 14 nM (n ϭ 5), 2.4 Ϯ 0.5 M (n ϭ 5), and 110 Ϯ 18 nM (n ϭ 5), respectively. Oral administration of Ro 32-7315 to Wistar rats caused a dose-dependent inhibition of LPS-induced release of systemic TNF-␣ with an ED 50 of 25 mg/kg. Treatment (days 0 -14) of Allen and Hamburys hooded rats with Ro 32-7315 (2.5, 5, 10, and 20 mg/kg, i.p., twice daily) significantly reduced adjuvant-induced secondary paw swelling (42, 71, 83, and 93%, respectively) as compared with the vehicle group. In the Ro 32-7315-treated group, the reduced paw swelling was associated with improved lesion score and joint mobility. Furthermore, in a placebocontrolled, single-dose study, Ro 32-7315 given orally (450 mg) significantly suppressed ex vivo, LPS-induced TNF-␣ release in the whole-blood samples taken from healthy male and female volunteers (mean inhibition of 42% over a 4-h duration, n ϭ 6). These data collectively support the potential use of such a compound for the oral treatment of inflammatory disorders.

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MMP Inhibitors Based on Earlier Succinimide Strategies: From Early to New Approaches

Santos¹

2009

Drug Design of Zinc‐Enzyme Inhibitors

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Anti-arthritic activity of hydroxamic acid-based pseudopeptide inhibitors of matrix metalloproteinases and TNFα processing

Abstract: Thus, these novel compounds offer a new disease modifying therapy for arthritis and the results also suggest that inhibition of TNF alpha production may contribute, at least in part, to their anti-arthritic activity.

Cited by 42 publications

References 13 publications

Human Mast Cell-Derived Gelatinase B (Matrix Metalloproteinase-9) Is Regulated by Inflammatory Cytokines: Role in Cell Migration

Human Mast Cell-Derived Gelatinase B (Matrix Metalloproteinase-9) Is Regulated by Inflammatory Cytokines: Role in Cell Migration

(E)-2(R)-[1(S)-(Hydroxycarbamoyl)-4-phenyl-3-butenyl]-2′-isobutyl-2′-(methanesulfonyl)-4-methylvalerohydrazide (Ro 32-7315), a Selective and Orally Active Inhibitor of Tumor Necrosis Factor-α Convertase

MMP Inhibitors Based on Earlier Succinimide Strategies: From Early to New Approaches

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