ONO 4817

ONO 4817 is a potent inhibitor of MMP-2, MMP-3, MMP-7, MMP-9, MMP-12 and MMP-13 with IC50 value of 0.73 nM, 42 nM, 2500 nM, 1.1 nM, 2.1 nM, 0.45 nM and 1.1 nM, respectively [1].

Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that belong to the metzincin superfamily and play an important role in tissue remodeling associated with various physiological or pathological processes such as morphogenesis, angiogenesis, tissue repair, cirrhosis, arthritis, and metastasis. It has been reported that MMPs involve in the tumor invasion and angiogenesis processes [1].

ONO 4817 is a potent MMP inhibitor and has a quite spread spectrum on MMP-2, MMP-3, MMP-7, MMP-9, MMP-12 and MMP-13, while has no effect on MMP-1 . When tested with the supernatant of lung cancer cell line PCI14PE6 cells, ONO 4817 caused the inhibition on the activities of MMP-2 and MMP-9 in a dose dependent manner (0.1-10 μM) [2].

In nude mice model with PC14 or PC14PE6 subcutaneous xenograft that produced metastasis only in the lungs, administration of ONO 4817 caused significant reduction of the number of lung metastasis, inhibited the formation of pleural effusion and decreased the tumor volumes [2]. In Sprague-Dawley rat model, ONO 4817 treatment (5 mg) significantly inhibited thickening of the submesothelial layer and accumulation of type I collagen in the peritoneum and prevented the increase of the number of macrophages and blood vessels [3].

References:
[1].  Okamoto, Y., et al., A matrix metalloproteinase inhibitor, ONO-4817, suppresses the development of aortic intimal hyperplasia in experimental hyperlipidemic rabbit. Int Heart J, 2007. 48(3): p. 369-78.
[2].  Shiraga, M., et al., Organ heterogeneity of host-derived matrix metalloproteinase expression and its involvement in multiple-organ metastasis by lung cancer cell lines. Cancer Res, 2002. 62(20): p. 5967-73.
[3].  Ro, Y., et al., Inhibitory effects of matrix metalloproteinase inhibitor ONO-4817 on morphological alterations in chlorhexidine gluconate-induced peritoneal sclerosis rats. Nephrol Dial Transplant, 2007. 22(10): p. 2838-48.

A matrix metalloproteinase inhibitor, ONO-4817, suppresses the development of aortic intimal hyperplasia in experimental hyperlipidemic rabbit.[Pubmed:17592201]

Int Heart J. 2007 May;48(3):369-78.

Inhibition of matrix metalloproteinases (MMPs) would be expected to suppress atherosclerotic neointimal proliferation and thus limit atheromatous plaque progression, but this has not yet been demonstrated morphologically in atherosclerotic intimal hyperplasia induced by cholesterol loading in experimental animals. We therefore investigated whether a broad-spectrum MMP inhibitor (MMPi), ONO-4817, could inhibit the development of intimal hyperplasia in male hyperlipidemic rabbits (n = 6) fed laboratory chow supplemented with 1% cholesterol for 2 months followed by a 1% cholesterol diet plus 100 mg/kg ONO-4817 for another month (Chol + ONO group). Control animals (n = 6) received no ONO-4817. When the aortas were studied both histologically and immunohistochemically, intimal hyperplasia was inhibited in Chol + ONO rabbits. The distribution of macrophages and MMP-12 in the hyperplastic tissue of the Chol + ONO rabbits was limited to the luminal side of the lesions. No such limitation in the distribution of macrophages and MMP-12 was observed in the control group. The distribution of smooth muscle cells in the hyperplastic tissue was not different between the Chol + ONO and control groups. However, the distribution of MMP-2 and MMP-12 was limited to the luminal side of lesions in the Chol + ONO group. This is the first reported evidence that an MMPi can suppress the development of intimal hyperplasia in hyperlipidemic rabbits.

Hepatic ischemia/reperfusion injury is prevented by a novel matrix metalloproteinase inhibitor, ONO-4817.[Pubmed:16701099]

Surgery. 2006 May;139(5):653-64.

BACKGROUND: Matrix metalloproteinases (MMPs) play an important role in inflammation and neoplastic invasion and metastasis. Little is known about the effects of MMP inhibitors on hepatic ischemia/reperfusion injury. The aim of this study is to examine the inhibitory effects of ONO-4817 (oral inhibitor of MMPs) in rats. METHODS: Hepatic ischemia/reperfusion was induced in male Wister rats by clamping the portal vein and hepatic artery. The animals were randomized into an ONO-4817 group (300 mg/kg body weight per/day) and a vehicle group by oral gavage of a test substance. Serum alanine aminotransferase, histologic changes, gelatinolytic activity, MMP-2 and MMP-9 activities, tissue inhibitor of metalloproteinase 2 (TIMP-2) messenger RNA (mRNA) levels, and mRNA and serum levels of tumor necrosis factor alpha (TNFalpha) and interleukin 1beta (IL-1beta) were measured in both groups. RESULTS: ONO-4817 prevented ischemia/reperfusion injury to the hepatocytes as shown by significant reductions of serum alanine aminotransferase and less severe histologic changes. Gelatinolytic activity was inhibited markedly in the liver of the ONO-4817 group as demonstrated by film in situ zymography. MMP-9 and MMP-2 activities also were inhibited in the ONO-4817 group as shown by gelatin zymography. TIMP-2 mRNA levels showed no significant differences between the 2 groups. TNFalpha mRNA showed no downregulation, but IL-1beta mRNA was downregulated in the liver of the ONO-4817 group 1 to 3 hours after reperfusion. Serum levels of TNFalpha and IL-1beta showed a significant decrease in the ONO-4817 group, compared with the vehicle group after reperfusion. CONCLUSIONS: Hepatic ischemia/reperfusion injury was improved by a novel MMP inhibitor, ONO-4817, not only by inhibition of gelatinolytic activity but also by a decrease in release of inflammatory cytokines.

Inhibitory effects of matrix metalloproteinase inhibitor ONO-4817 on morphological alterations in chlorhexidine gluconate-induced peritoneal sclerosis rats.[Pubmed:17545675]

Nephrol Dial Transplant. 2007 Oct;22(10):2838-48.

BACKGROUND: The activity of gelatinase, matrix metalloproteinase-2, in effluent was increased in peritoneal dialysis patients with encapsulated peritoneal sclerosis (EPS) and in chlorhexidine gluconate-induced peritoneal sclerosing (PS) animal models. The objective of the present study was to investigate the effect of matrix metalloproteinase inhibitor (ONO-4817), an anticancer agent with anti-angiogenesis and anti-infiltration effects, on the development of peritoneal fibrosis in chlorhexidine gluconate-induced PS rats. METHODS: Forty-five Sprague-Dawley (S-D) rats were intraperitoneally injected with saline as control (n = 15) or with chlorhexidine gluconate (CH) (1.5 ml/100 g) in the CH group (n = 15). ONO-4817 (5 mg/rat) was administered intravenously to CH rats (the ONO-4817 group, n = 15) from initiation to the end of the study. After 22 days of ONO-4817 administration, the rats were sacrificed and the parietal peritoneum was harvested. The gene expressions of transforming growth factor-beta (TGF-beta), alpha-smooth muscle actin (alpha-SMA) and type I collagen in the peritoneum were analysed by the reverse transcription-polymerase chain reaction (RT-PCR). Peritoneal tissues were also evaluated immunohistologically. RESULTS: ONO-4817 significantly inhibited thickening of the submesothelial layer and accumulation of type I collagen in the peritoneum. ONO-4817 also prevented increases of the number of macrophages and blood vessels. The expressions of TGF-beta, alpha-SMA and type I collagen in the peritoneum were markedly suppressed in ONO-4817-treated rats. CONCLUSION: It appears that the administration of the MMP inhibitor ONO-4817 might be a new approach to the amelioration of PS.

Matrix metalloproteinase inhibitor (ONO-4817) attenuates ischemia-reperfusion injury in rat lung.[Pubmed:16449942]

Med Sci Monit. 2006 Feb;12(2):BR51-6. Epub 2006 Jan 26.

BACKGROUND: Ischemia-reperfusion injury of the lungs seems to be initiated by the activation of alveolar macrophages, and mediated by matrix metalloproteinases (MMP)s, although their roles have not been fully elucidated. Therefore, we used a novel MMP inhibitor (ONO-4817) with high affinities for MMP-2 and MMP-9 to investigate the roles of MMPs in reperfusion injury of the lungs. MATERIAL/METHODS: After 18 h of cold ischemia, isolated rat lungs were ventilated and reperfused. Lungs without ischemia served as controls. Lungs were reperfused with fresh blood with or without the MMP inhibitor for 120 min at 37 degrees C. RESULTS: The oxygenation capacity of lungs after ischemia deteriorated progressively during 120 min of reperfusion, but was preserved by the MMP inhibitor (p<0.05). The histopathology of the lungs after ischemia-reperfusion showed interstitial edema accompanied by neutrophil migration, and the number of neutrophils, but not macrophages, in the broncho-alveolar lavage increased to more than two-fold the value in control lungs without ischemia (p<0.01). These changes were attenuated by the MMP inhibitor (p<0.01). Similarly, an increase in the tissue malondialdehyde level in lungs after ischemia-reperfusion was ameliorated by the MMP inhibitor (p<0.01). The expressions of CD11c and CD31 adhesion molecules in extracted alveolar macrophages increased in lungs after ischemia-reperfusion compared with control lungs without ischemia, and the MMP inhibitor had no obvious effect. CONCLUSIONS: Our data show that ONO-4817 prevented neutrophil migration into the interstitial space and alveolus in the lungs, and reduced the production of oxygen free radicals, suggesting that this is an important mechanism in reperfusion injury.

Role of matrix metalloproteinases in intestinal inflammation.[Pubmed:16644899]

J Pharmacol Exp Ther. 2006 Sep;318(3):933-8.

Matrix metalloproteinases (MMPs) and their endogenous inhibitors, tissue inhibitors of MMPs (TIMPs), are produced in the gastrointestinal tract by several structural cells. The balance between MMPs and TIMPs is essential for many physiological processes in the gut. However, imbalance between MMPs and TIMPs plays an important role in the pathophysiology of diverse intestinal inflammatory conditions. We reviewed the role of the MMP/TIMP system in the pathogenesis of intestinal inflammatory diseases and pharmacologic perspectives for the use of compounds that restore the MMP/TIMP balance.

Effect of a matrix metalloproteinase inhibitor (ONO-4817) on lung metastasis of murine renal cell carcinoma.[Pubmed:11911256]

Anticancer Res. 2001 Nov-Dec;21(6A):3845-52.

We examined the anti-metastatic effect of a newly developed inhibitor of synthetic matrix metalloproteinase (MMP), ONO-4817, on experimental pulmonary metastasis of murine renal cell carcinoma (Renca) cells and on tumor cell invasion, through reconstituted basement membrane (Matrigel) in vitro using the same cells. Oral administration of ONO-4817 (50-200 mg/kg/day) to Renca-bearing mice resulted in a dose-dependent inhibition of lung metastasis without a loss of body weight. ONO-4817 at the high dose of 200 mg/kg showed a tendency to prolong the survival of the mice. We also found that oral administration of ONO-4817 significantly inhibited the angiogenic response (number of vessels oriented towards the tumor mass) and the growth of tumors inoculated i.d. in syngeneic mice. In addition, ONO-4817, at non-cytotoxic concentrations of less than 10 microM, caused a marked inhibition of the invasion of Renca cells as compared to the vehicle control. Gelatin zymography revealed that ONO-4817 inhibited the enzymatic activity of MMP-2 produced by Renca cells in a concentration-dependent manner. In conclusion, ONO-4817 effectively inhibited lung metastasis of Renca cells through its anti-invasive and anti-angiogenic properties. These results suggest that use of the MMP inhibitor (MMPI) ONO-481 7 may provide a therapeutic basis for preventing lung recurrence and metastasis of renal cell carcinoma.

ONO-4817, an orally active matrix metalloproteinase inhibitor, prevents lipopolysaccharide-induced proteoglycan release from the joint cartilage in guinea pigs.[Pubmed:10858013]

Inflamm Res. 2000 Apr;49(4):144-6.

OBJECTIVE AND DESIGN: To evaluate the effect of a newly developed inhibitor of matrix metalloproteinases (MMPs), ONO-4817, on the degradation of cartilage in the guinea pig arthritis model. MATERIALS: 42 guinea pigs were used in the arthritis model. TREATMENT: Lipopolysaccharide (LPS) was injected into guinea pig knee joints. The content of proteoglycan released in synovial cavity was measured as a marker of cartilage degradation. ONO-4817, dexamethasone or indomethacin were administered orally to the animals. RESULTS: ONO-4817 showed a broad inhibitory activity against MMPs except MMP-1 and MMP-7. The oral administration of ONO-4817 dose-dependently suppressed the release of proteoglycan from the cartilage of the knee joints. CONCLUSION: This study suggests the possibility that a novel MMP inhibitor, ONO-4817 may have a therapeutic utility for MMP-related diseases.