New Orally Active Serine Protease Inhibitors

Senokuchi, Kazuhiko; Nakai, Hisao; Nakayama, Y.; Odagaki, Yoshihiko; Sakaki, Katsuhito; Kato, Masashi; Maruyama, Toru; Miyazaki, Tôru; Ito, Hidenori; Kamiyasu, Koumei; Kim, Soonih; Kawamura, Masanori; Hamanaka, Nobuyuki

doi:10.1021/jm00014a003

Cited by 32 publications

(20 citation statements)

References 3 publications

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“…ONO 3403, a derivative of camostat mesilate, has a higher protease-inhibitory activity than camostat mesilate (FOY 305). 9 ONO 3403 exhibited anti-inflammatory activity at a lower concentration than camostat mesilate (FOY 305). ONO 3403 almost completely inhibits augmentation of the serine protease activity in response to LPS.…”

Section: Discussionmentioning

confidence: 99%

“…7,8 Recently, orally active ONO 3403 has been produced as an analog of camostat mesilate (FOY 305) with more potent protease-inhibitory activity against various proteases, such as trypsin, plasmin, thrombin, urokinase-type plasminogen activator and plasma kallikrein. 9,10 However, there is no report on the anti-inflammatory action of ONO 3403 with a higher protease-inhibitory activity. It is of interest to characterize the relationship between anti-protease-inhibitory activity and anti-inflammatory activity of ONO 3403.…”

Section: Introductionmentioning

confidence: 99%

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ONO 3403, a synthetic serine protease inhibitor, inhibits lipopolysaccharide-induced tumor necrosis factor-α and nitric oxide production and protects mice from lethal endotoxic shock

et al. 2009

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ONO 3403, a new synthetic serine protease inhibitor, is a derivative of camostat mesilate and has a higher protease-inhibitory activity. The effect of ONO 3403 on lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-α and nitric oxide (NO) production in RAW 264.7 macrophage-like cells was examined. ONO 3403 significantly inhibited LPS-induced TNF-α production at a lower concentration than camostat mesilate. It also inhibited LPS-induced NO production. Their inhibition was responsible for the reduced mRNA expression of TNF-α and inducible NO synthase. In LPS-stimulated cells, ONO 3403 prevented the augmentation of MyD88 expression and inhibited the phosphorylation of IκB-α, stress-activated protein kinase (SAPK) and IRF-3, and the production of interferon-β. ONO 3403 abolished the elevation of the extracellular serine protease activity in response to LPS. Further, it reduced the circulating TNF-α level, hepatic injury and mortality in mice receiving an injection of D-galactosamine and LPS. ONO 3403 was suggested to inhibit LPS-induced inflammatory responses via inactivation of MyD88-dependent and independent pathways.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

ONO 3403, a synthetic serine protease inhibitor, inhibits lipopolysaccharide-induced tumor necrosis factor-α and nitric oxide production and protects mice from lethal endotoxic shock

et al. 2009

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“…These compounds as well as FOY-305 also inhibit thrombin, kallikrein and plasmin but less effectively. 4 Study on the growth-inhibitory effects of these protease inhibitors has revealed that only ONO-3403 induces apoptosis-like cell death. Further biochemical analysis suggested that this effect of ONO-3403 is related to its stimulatory activity toward calpain.…”

Section: Introductionmentioning

confidence: 99%

Induction of apoptosis by a calpain stimulator, ONO-3403

Hiwasa

1996

Apoptosis

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The effects of a synthetic serine proteese inhibitor, FOY-305, and its derivatives, ONO-3403 and FO-349, on the proliferation of mouse NIH3T3 cells were investigated. At concentrations between 10 and 100 ~g/ml, three protease inhibitors induced a moderate suppression of cell growth. However, only ONO-3403 showed severe cytotoxicity at concentrations higher than 200 ~g/ml. Results of TUNEL staining and DNA fragmentation analysis indicated that ONO-3403 induced apoptosis at the high concentrations. Biochemical analysis has shown that ONO-3403 directly enhanced the amidolytic activity of purified ~-calpain at a concentration higher than 100 ~g/ml while FOY-305 and FO-349 showed less effects. When the cell extract was incubated in the presence of ONO-3403, specific degradation of a few proteins including protein kinase C was observed. Similar degradation was also observed by addition of ~-calpain to the extract. These results imply that ONO-3403 is a specific stimulator of calpain. It seems reasonable to conclude that increase in calpain activity results in apoptosis.

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“…Five trypsin inhibitors served as reference compounds for DOGS design runs (Camostat [45], NAPAMP [46], Efegatran [47], Patamostat [48], [49], UK-156406 [50]). …”

Section: Resultsmentioning

confidence: 99%

DOGS: Reaction-Driven de novo Design of Bioactive Compounds

et al. 2012

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We present a computational method for the reaction-based de novo design of drug-like molecules. The software DOGS (Design of Genuine Structures) features a ligand-based strategy for automated ‘in silico’ assembly of potentially novel bioactive compounds. The quality of the designed compounds is assessed by a graph kernel method measuring their similarity to known bioactive reference ligands in terms of structural and pharmacophoric features. We implemented a deterministic compound construction procedure that explicitly considers compound synthesizability, based on a compilation of 25'144 readily available synthetic building blocks and 58 established reaction principles. This enables the software to suggest a synthesis route for each designed compound. Two prospective case studies are presented together with details on the algorithm and its implementation. De novo designed ligand candidates for the human histamine H4 receptor and γ-secretase were synthesized as suggested by the software. The computational approach proved to be suitable for scaffold-hopping from known ligands to novel chemotypes, and for generating bioactive molecules with drug-like properties.

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New Orally Active Serine Protease Inhibitors

Cited by 32 publications

References 3 publications

ONO 3403, a synthetic serine protease inhibitor, inhibits lipopolysaccharide-induced tumor necrosis factor-α and nitric oxide production and protects mice from lethal endotoxic shock

ONO 3403, a synthetic serine protease inhibitor, inhibits lipopolysaccharide-induced tumor necrosis factor-α and nitric oxide production and protects mice from lethal endotoxic shock

Induction of apoptosis by a calpain stimulator, ONO-3403

DOGS: Reaction-Driven de novo Design of Bioactive Compounds

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