Inhibitory Effect of a New Synthetic Protease Inhibitor (FUT-175) on the Coagulation System

Hitomi, Yuji; Ikari, Nobuhiko; Fujii, Susumu

doi:10.1159/000215139

Cited by 85 publications

(82 citation statements)

References 9 publications

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“…Nafamostat mesilate is capable of inhibiting other serine proteases, including trypsin and some proteases that are involved in the coagulation process. [31][32][33] In addition, nafamostat mesilate can decrease the activity levels of MMPs. 26,27) Nafamostat mesilate per se exhibited no significant morphological changes in retina.…”

Section: Discussionmentioning

confidence: 99%

Effect of Nafamostat on N-Methyl-D-aspartate-Induced Retinal Neuronal and Capillary Degeneration in Rats

Tsuda

Nakahara

Ueda

et al. 2012

Biological & Pharmaceutical Bulletin

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We examined the effects of the serine protease inhibitor nafamostat mesilate on neuronal and vascular injury in rat retinas treated with N-methyl-D-aspartate (NMDA). The degree of neuronal degeneration was assessed by measuring the number of cells in the ganglion cell layer and the thickness of the inner plexiform layer. The degree of capillary degeneration was assessed by measuring the number of empty basement membrane sleeves that were left as remnants of the vessels. Significant neuronal and capillary degeneration was observed 7 d after a single intravitreal injection of NMDA into the eye. Both forms of degeneration were significantly prevented by simultaneous injection of nafamostat mesilate with NMDA. These results indicate that nafamostat mesilate affords protection against the neuro/vascular injury seen in NMDA-treated retinas. Nafamostat mesilate may be considered as a candidate for neuro/vascular protective interventions in retinal diseases associated with glutamate-induced excitotoxicity, such as glaucoma and diabetic retinopathy.Key words endothelial cell; excitotoxicity; retinal blood vessel; retinal degeneration Neuronal injury and death play a critical role in the pathogenesis of retinal diseases such as diabetic retinopathy and glaucoma. Glutamate-induced excitotoxicity appears to play an important role in these retinal diseases. -activated proteolytic enzymes, including calpains.6,7) In addition, upregulation of pro-inflammatory cytokines and inflammatory adhesion molecules, 8,9) increase in matrix metalloproteinase (MMP) activity, [10][11][12] and recruitment of leukocytes into the retina 8) are also involved. These events precede the occurrence of retinal ganglion cell apoptosis, and preventive interventions have been shown to ameliorate NMDA-induced retinal ganglion cell death. Thus, excessive activation of NMDA receptors appears to affect retinal neuronal cell survival by indirect as well as direct mechanisms.A single intravitreal injection of NMDA into the eye is commonly used in vivo model to induce different forms of retinal damage, such as retinal ganglion cell apoptosis, thinning of the inner retina, and visual dysfunction. 13,14) More recently, injury to the retinal microvasculature, including capillary degeneration, has also been demonstrated in the same model. 15,16) Pathological changes in retinal circulation could contribute to the progression of retinal diseases, including diabetic retinopathy and glaucoma.17-21) Therefore, the NMDA-induced retinal injury model would be useful for screening novel interventions and approaches for treating such retinal diseases by protecting from neuro/vascular injury.Nafamostat mesilate (FUT-175, 6-amidino-2-napthyl-4-guanidinobenzoate) was originally developed as a complement inhibitor 22) and is used for the treatment of pancreatitis and disseminated intravascular coagulation.23,24) Nafamostat mesilate has also been shown to exert broad inhibitory effects against serine proteases, especially tryptase, 25) and decrease activities of MMP-9. 26,27) T...

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Section: Discussionmentioning

confidence: 99%

Effect of Nafamostat on N-Methyl-D-aspartate-Induced Retinal Neuronal and Capillary Degeneration in Rats

Tsuda

Nakahara

Ueda

et al. 2012

Biological & Pharmaceutical Bulletin

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“…Equilibrium constants for acetone, pyruvic acid, and methyl pyruvate are taken from the literature. 23 The hydration equilibrium constant for cyclohexanone is 35 times greater than that of acetone. In cyclohexanone, ring strain preparation of each of the four target compounds.…”

Section: Resultsmentioning

confidence: 99%

“…The retention times for diastereomers 32a and 32b"were 13.1 and 14.1 min, respectively. For 32a: »H NMR (400 MHz, CDC1 3 18 - 23 Cyclohexanone, tetrahydropyran-4-one, tetrahydrothiopyran-4-one, and 4-piperidone hydrochloride were purchased from Aldrich Chemical Co. and used without further purification. NMR samples were prepared by dissolving the ketone (100 mM) in D 2 0.…”

Section: Methodsmentioning

confidence: 99%

Anticancer Agents Based on a New Class of Transition- State Analog Inhibitors for Serine and Cysteine Proteases

Seto¹

1999

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewingjnstructions.searching existing data sources, aatnerinoi and maintaining the data needed, and completing and reviewing the collection of information. Send comments regarding this burden estimate or any other aspect ofthis collection of information, including suggestions for reducing this burden. 1o Washington Headquarters Services, Directorate Tor Information Operations and Reports, 1215 Jefferson Davis Highway Suite1204, Arlington, VA 22202-4302, and to the Of/ice of Management and Budget, Paperwork Reduction Project (0704-0188), Washington, DC 20503. AGENCY USE ONLY (Leave blank)2. REPORT DATE August 1999 REPORT TYPE AND DATES COVERED PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES)Brown University Providence, RI 02912 SPONSORING/MONITORING AGENCY NAME(S) AND ADDRESS(ES)Commander ABSTRACT (Maximum 200In this report we describe our efforts to develop a new class of competitive inhibitors for serine and cysteine proteases. These compounds are potential anticancer agents that would act by inhibiting metastasis and angiogenesis. Our work has shown that the 4-heterocyclohexanone pharmacophore can be used to synthesize effective inhibitors of both serine and cysteine proteases. We have rationally designed an inhibitor of the serine protease plasmin, and shown that it has good activity and specificity for plasmin over other proteases. In addition, we have used the 4-heterocyclohexanone pharmacophore to construct a combinatorial library of 400 different protease ^ inhibitors. These compounds are unique in that they are designed to interact with both the S and S binding sites of proteases; a feature which will increase both their potency and specificity. The library was screened against a variety of cancer-related proteases, which lead us to identify a second, even more potent inhibitor of plasmin. Where copyrighted material is quoted, permission has been obtained to use such material. SUBJECT TERMS Breast CancerWhere material from documents designated for limited distribution is quoted, permission has been obtained to use the material.Citations of commercial organizations and trade names in this report do not constitute an official Department of Army endorsement or approval of the products or services of these organizations.In conducting research using animals, the investigator(s) adhered to the "Guide for the Care and Use of Laboratory Animals," prepared by the Committee on Care and use of Laboratory Animals of the Institute of Laboratory Resources, national Research Council (NIH Publication No. 86-23, Revised 1985).For the protection of human subjects, the investigator(s) adhered to policies of applicable Federal Law 45 CFR 46.In conducting research utilizing recombinant DNA technology, the investigator(s) adhered to current guidelines promulgated by the National Institutes of Health.In the conduct of research utilizing recombinant DNA, the investigator(s) adhered to the NIH Guide...

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“…In addition, NM improved DIC in the experimental animal models (Yoshikawa et al 1983;Koshiyama et al 1987), and had anticoagulant effects in vitro (Uchiba et al 1994) and in humans Hitomi et al 1985). In this connection, NM has been used for the treatment of DIC (Shibata et al 1988;Okamoto et al 1991), as well as for extracorporeal circulation (Tsukagoshi et al 2000) and hemodialysis (Pak et al 1988) Such off-label use of the drug has advantages over developing a new drug in terms of saving the time until application to humans and of the logistics: the clinical use of an already approved drug for symptomatic treatment would not be associated with any major ethical problems, although there may have some restrictions.…”

Section: Introductionmentioning

confidence: 95%

“…And NM inhibits kallikrein ) and the factor VIIa complex (Uchiba et al 1994), one of proteases associated with the pathogenesis of DIC, and has other anti-coagulant effects (Hitomi et al 1985). This drug has been widely used in the clinical setting in Japan for the treatment of DIC (Okamoto et al 1991).…”

Section: Management Of Dic In Evdmentioning

confidence: 99%

A Synthetic Serine Protease Inhibitor, Nafamostat Mesilate, Is a Drug Potentially Applicable to the Treatment of Ebola Virus Disease

Nishimura

Yamaya

2015

Tohoku J. Exp. Med.

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Ebola virus disease (EVD) has been a great concern worldwide because of its high mortality. EVD usually manifests with fever, diarrhea and vomiting, as well as disseminated intravascular coagulation (DIC). To date, there is neither a licensed Ebola vaccine nor a promising therapeutic agent, although clinical trials are ongoing. For replication inside the cell, Ebola virus (EBOV) must undergo the proteolytic processing of its surface glycoprotein in the endosome by proteases including cathepsin B (CatB), followed by the fusion of the viral membrane and host endosome. Thus, the proteases have been considered as potential targets for drugs against EVD. However, no protease inhibitor has been presented as effective clinical drug against it. A synthetic serine protease inhibitor, nafamostat mesilate (NM), reduced the release of CatB from the rat pancreas. Furthermore, it has anticoagulant activities, such as inhibition of the factor VIIa complex, and has been used for treating DIC in Japan. Thus, NM could be considered as a drug candidate for the treatment of DIC induced by EBOV infection, as well as for the possible CatB-related antiviral action. Moreover, the drug has a history of large-scale production and clinical use, and the issues of safety and logistics might have been cleared. We advocate in vitro and in vivo experiments using active EBOV to examine the activities of NM against the infection and the DIC induced by the infection. In addition, we suggest trials for comparison among anti-DIC drugs including the NM in EVD patients, in parallel with the experiments.

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Inhibitory Effect of a New Synthetic Protease Inhibitor (FUT-175) on the Coagulation System

Cited by 85 publications

References 9 publications

Effect of Nafamostat on <i>N</i>-Methyl-<small>D</small>-aspartate-Induced Retinal Neuronal and Capillary Degeneration in Rats

Effect of Nafamostat on <i>N</i>-Methyl-<small>D</small>-aspartate-Induced Retinal Neuronal and Capillary Degeneration in Rats

Anticancer Agents Based on a New Class of Transition- State Analog Inhibitors for Serine and Cysteine Proteases

A Synthetic Serine Protease Inhibitor, Nafamostat Mesilate, Is a Drug Potentially Applicable to the Treatment of Ebola Virus Disease

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