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Edaravone is a low-molecular-weight antioxidant drug targeting peroxyl radicals among many types of reactive oxygen species. Because of its amphiphilicity, it scavenges both lipid- and water-soluble peroxyl radicals by donating an electron to the radical. Thus, it inhibits the oxidation of lipids by scavenging chain-initiating water-soluble peroxyl radicals and chain-carrying lipid peroxyl radicals. In 2001, it was approved in Japan as a drug to treat acute-phase cerebral infarction, and then in 2015 it was approved for amyotrophic lateral sclerosis (ALS). In 2017, the U.S. Food and Drug Administration also approved edaravone for treatment of patients with ALS. Its mechanism of action was inferred to be scavenging of peroxynitrite. In this review, we focus on the radical-scavenging characteristics of edaravone in comparison with some other antioxidants that have been studied in clinical trials, and we summarize its pharmacological action and clinical efficacy in patients with acute cerebral infarction and ALS.

The etiology of amyotrophic lateral sclerosis (ALS) is unknown. Oxidative stress may be one of the major mechanisms involved. In vitro and in vivo data of edaravone suggest that it may possess broad free radical scavenging activity and protect neurons, glia, and vascular endothelial cells against oxidative stress. During the 1980s and 1990s, edaravone was developed for the treatment of acute ischemic stroke. In 2001, a clinical program in ALS was initiated and five clinical studies were conducted in Japan. Phase III studies were designed to rapidly evaluate (within a 24-week double-blind study window) functional changes using the Revised ALS Functional Rating Scale (ALSFRS-R) as a primary endpoint. The study populations were selected according to these considerations and were further refined as the studies proceeded. Although the first phase III study did not meet its primary endpoint, post-hoc analyses showed an apparent effect of edaravone, when additional patient inclusion criteria defined by ALSFRS-R score, pulmonary function, certainty of ALS diagnosis, and duration of disease were applied. This population was hypothesized not only to have retained broad functionality and normal respiratory function at study baseline but also to be likely to show measurable disease progression over 24 weeks. A second confirmatory phase III study applying these refinements in patient selection was prospectively designed and successfully documented a statistically significant difference between the edaravone and placebo groups in the ALSFRS-R primary endpoint. This paper describes and reviews data pertinent to the potential mechanism of action of edaravone, and reviews the development history of edaravone for the treatment of ALS.

The base-induced Sommelet–Hauser (S–H) rearrangement of azetidine-2-carboxylic acid ester-derived ammonium salts into 2-aryl-substituted derivatives was demonstrated. The ring-strain of four-membered N-heterocycles enables efficient generation of the desired ylide intermediate and enhances the rate of the S–H rearrangement. The asymmetric version of the rearrangement was characterized by excellent levels of successive chirality transmissions. The regio- and stereo-controlled nucleophilic ring opening of the rearrangement products produced quaternary α-aryl amino acid esters with excellent enantiopurities.

We herein describe the results of further evolution of glycogen synthase kinase (GSK)-3β inhibitors from our promising compounds containing a 3-methylmorpholine moiety. Transformation of the morpholine moiety into a piperazine moiety resulted in potent GSK-3β inhibitors. SAR studies focused on the nitrogen atom of the piperazine moiety revealed that a phenyl group afforded potent inhibitory activity toward GSK-3β. Docking studies indicated that the phenyl group on the piperazine nitrogen atom and the methyl group on the piperazine make cation-π and CH-π interactions with GSK-3β respectively. 4-Methoxyphenyl analogue 29 showed most potent inhibitory activity toward GSK-3β with good in vitro and in vivo pharmacokinetic profiles, and 29 demonstrated a significant decrease in tau phosphorylation after oral administration in mice.

We herein describe the results of further evolution of glycogen synthase kinase (GSK)-3β inhibitors from our promising compounds containing a 2-phenylmorpholine moiety. Transformation of the morpholine moiety into a piperazine moiety resulted in potent GSK-3β inhibitors. SAR studies focused on the phenyl moiety revealed that a 4-fluoro-2-methoxy group afforded potent inhibitory activity toward GSK-3β. Based on docking studies, new hydrogen bonding between the nitrogen atom of the piperazine moiety and the oxygen atom of the main chain of Gln185 has been indicated, which may contribute to increased activity compared with that of the corresponding phenylmorpholine analogues. Effect of the stereochemistry of the phenylpiperazine moiety is also discussed.

A series of 2-(2-phenylmorpholin-4-yl)pyrimidin-4(3H)-ones was synthesized and examined for their inhibitory activity against glycogen synthase kinase-3β (GSK-3β). We found 21, 29 and 30 to possess potent in vitro GSK-3β inhibitory activity with good in vitro PK profiles. 21 demonstrated significant decrease of tau phosphorylation after oral administration in mice and excellent PK profiles.

Simplified reaction models were developed theoretically and experimentally for use in the computational fluid dynamics of Gallium Nitride (GaN) growth in metal organic vapor-phase epitaxy (MOVPE). The activation energy of various elementary reaction pathways in a trimethylgallium/ammonia /hydrogen (Ga(CH3)3/NH3/H2) system were calculated using an ab-initio molecular orbital (MO) method. Then, the dominant steps of the reaction paths and the respective activation energies were obtained using the following reactions: Ga(CH3)3 + NH3 → Ga(CH3)2NH2 (Ea = 1.3 eV), 2Ga(CH3)2NH2 →[Ga(CH3)2NH2 ] 2 + 2CH4 (Ea = 0 eV), Ga(CH3)2NH2 → GaN + 2CH4 (Ea = 3.0 eV). The computational fluid dynamics performed using our reaction-model agreed well with the experimental results for the distribution of the GaN growth rate under this study's growth conditions.

収穫後青果物のエチレン処理が貯蔵中の高温耐性に及ぼす影響を議論するため，制御された環境で栽培されたリョクトウモヤシ葉部をエチレン処理した後に高温処理し，外観と生理的特性の変化を調べた．エチレン濃度50 ppmで3日間前処理すると，高温ストレス環境（50℃，120分）曝露後の葉部における壊死発生（外観品質の低下）の遅延と軽減が誘導された．さらに，エチレン処理することによって，50℃，60分の高温ストレス環境下におけるイオン漏出割合（イオンの膜透過性）の抑制が観察された．一方，呼吸速度や膜脂質の過酸化程度には，エチレン前処理の影響は見いだされなかった．これらの結果は，リョクトウモヤシに対する収穫後のエチレン処理によって，高温ストレス耐性が誘起されることを示しており，エチレンには高温障害に関連する膜損傷を軽減する作用があることが示唆された．以上の知見は，収穫後青果物の高温障害の抑制に対するエチレンの効用を検討することの重要性を示唆している．

An asymmetric synthesis of 2-arylpiperazines starting from phenacyl bromides, a variety of which are easily available, has been established. The synthesis features a CBS reduction of phenacyl bromide to provide optically enriched compounds, an SN2 reaction of 1,2,3-oxathiazolidine 2-oxides with an azide anion with invert of configuration, and construction of the piperazine ring via reduction of piperazine-2,3-diones.

We investigated the properties of Ge-doped, high-quality bulk GaN crystals with Ge concentrations up to 2.4×10 19 cm −3 . The Ge-doped crystals were fabricated by hydride vapor phase epitaxy with GeCl 4 as the dopant source. Cathodoluminescence imaging revealed no increase in the dislocation density at even the highest Ge concentration, with values as low as 3.4×10 6 cm −2 . The carrier concentration, as determined by Hall measurement, was almost identical to the combined concentration of Ge and unintentionally incorporated Si. The electron mobilities were 260 and 146 cm 2 V −1 s −1 for n =3.3×10 18 and 3.35×10 19 cm −3 , respectively; these values are markedly larger than those reported in the past for Ge-doped GaN thin films. The optical absorption coefficient was quite small below the band gap energy; it slightly increased with increase in Ge concentration. Thermal conductivity, estimated by the laser-flash method, was virtually independent of Ge concentration, maintaining an excellent value around 2.0 W cm −1 K −1 . Thermal expansion coefficients along the a - and m -axes were approximately constant at 5.0×10 −6 K −1 in the measured doping concentration range.

The free radical scavenger 3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone) has been used to treat acute brain infarction in Japan since 2001. To obtain direct evidence that edaravone serves as an antioxidant in vivo, four groups of rats were prepared: (i) an ischemia/reperfusion (I/R) group receiving 2 h occlusion-reperfusion of the middle cerebral artery; (ii) a single administration group treated by intravenous infusion of edaravone (3 mg/kg) immediately after I/R; (iii) a repeated treatment group receiving twice daily edaravone administration for 14 days; and (iv) a sham operation group without occlusion. Repeated treatment with edaravone significantly improved the neurological symptoms and impairment of motor function as compared to the I/R group, while single administration demonstrated limited efficacy. No significant differences in plasma antioxidants such as ascorbate, urate, and vitamin E, or in redox status of coenzyme Q(9) were observed among the four groups. In contrast, the plasma content of oleic acid in the total free fatty acids (percentage 18:1) was significantly increased in the I/R group for 7 days as compared to the sham operation group. Oleic acid was produced from stearic acid by the action of stearoyl-CoA desaturase to compensate for the oxidative loss of polyunsaturated fatty acids. The above results suggest that cellular oxidative damage in the rat brain is evident for at least 7 days after I/R. Repeated treatment suppressed the percentage 18:1 increment, while the single administration did not, which is consistent with the limited efficacy of single administration.

Two metabolites of a free radical scavenger, edaravone, were synthesized. Edaravone glucuronate was synthesized by glycosylation of a glucuronic acid precursor using silver (I) trifluoromethane-sulfonate with edaravone. Edaravone sulfate was synthesized by sulfonylation of edaravone using a sulfur trioxide-pyridine complex. The two synthesized metabolites were identical to isolated metabolites. X-ray analysis identified edaravone glucuronate as beta-O-glucuronate, although there were three possible edaravone glucuronate tautomers.

By using the hydride vapor phase epitaxy and a void-assisted separation method, freestanding 3-in GaN substrates were successfully fabricated for the first time, and the process showed an excellent reproducibility. A thick GaN layer 3.2 in in diameter was easily separated from the base substrate. No cracks were generated during the separation process. The dislocation density was of the order of 10 6 cm –2 . The carrier density was approximately 1×10 18 cm –3 and the mobility was 3.4×10 2 cm 2 V –1 s –1 . The concentrations of impurities, estimated by secondary-ion mass spectrometry, were below the limit of detection, except for Si. The Si concentration was approximately 1×10 18 cm –3 , which is in good agreement with the carrier density.

Free radical-induced oxidation of an anti-ischemic agent, 3-methyl-l-phenyl-2-pyrazolin-5-one (MCl-186) gave 2-oxo-3- (phenylhydrazono) -butanoic acid as the final product via 3-methyl-1-phenyl-2-pyrazolin-4, 5-dione and 4-hydroxy-4- (3-methyl-1-phenyl-2-pyrazolin-5-on-4-yl) -3-methyl-1-phenyl-2-pyrazolin-5-one as intermediates regardless of the free radical source. The mechanism for product formation is discussed.

The discovery of a series of 6-(4-pyridyl)pyrimidin-4(3H)-ones derived from a hit compound with low molecular weight and sufficient chemical space is reported. Transformation of substituents led to subnanomolar potent inhibitors with in vivo tau phoshorylation lowering activity.

In order to clalify the species difference in metabolism of MCI-186, the identification of metabolites, urinary excretion rates of unchanged MCI-186 and its metabolites, and in vitro metabolism were investigated in rats, dogs and human. 1. Main metabolites of MCI-186 were sulfate and glucuronide of MCI-186 in all species. In the urine of rats and dogs, excretion rates of sulfate were higher than those of glucuronide, however in the urine of human, excretion rate of glucuronide was higher than that of sulfate, therefore species difference was observed in urinary excretion. 2. Urinary excretion was the main excretion route in all species. Excretion rates of the unchanged MCI-186 to urine were less than 3 % of dose. In dogs and human, urinary excretion can be mostly explained by excretion of unchanged MCI-186, and its sulfate and glucuronide. However in rats, unknown metabolites were present at higher rates of 20 ?? 27% of the urinary radioactivities. And sex difference in urinary excretion was not observed mostly in rats. 3. Activities of formation of MCI-186 sulfate were higher than those of MCI-186 glucuronide at in vitro metabolism of MCI-186 with liver S9 of rats and dogs. And both activities were higher in male rats than in female rats.

食品のタンパク質のグリケーションの程度は,フルクトシルリジンやラクチュロシルリジンなどアマドリ化合物を含むタンパク質の酸加水分解により生成する,フロシンの定量によって行なうことができる.本実験では,フロシンを効率的に生成する加水分解条件およびカウンターイオンとしてSDSを用いた逆相系HPLCによるフロシンの分析法について検討した.その結果,フロシンの生成の最適条件の設定と共に,フロシンの定量を約15分で効率よく行なう方法を開発した.本法を用いて,乳および乳製品タンパク質のグリケーションの程度を調べた結果,スキムミルク,乳児用調整粉乳および原料に脱脂粉乳を用いた発酵乳において高い値を示した.

A series of 5-phenyl-substituted-N-alkyl-imidazolin-2-ones with potent radical-scavenging activity and lipid peroxidation inhibitory activity was synthesized. Many of the compounds showed memory-improving effect in animal models independent of the inhibitory activity on lipid peroxidation.

Increasing data suggest that oxygen free radical species play detrimental roles in ischemic diseases. A free radical scavenger capable of inhibiting oxidative injury is expected to become a new drug for the treatment of ischemic diseases such as cerebral ischemia. Edaravon (3-methyl-1-phenyl-2-pyrazolin-5-one), which has been developed as an neuroprotective agent for more than 15 years since its discovery, is approved for the treatment of acute cerebral infarction. In this paper, the pharmacologic characteristics and clinical effects of edaravone are reviewed. In early stage of investigation, edaravone was found to have promising activities as an antioxidative radical scavenger, quenching hydroxyl radical (.OH) and inhibiting both .OH-dependent and .OH-independent lipid peroxidation. Edaravone showed inhibitory effects on both water-soluble and lipid-soluble peroxyl radical-induced peroxidation systems, which are different from the inhibitory effects of vitamins C and E in each system, respectively. Oxidative injury to cultured endothelial cells caused by arachidonate (AA) peroxides is prevented in the existence of edaravone. To clarify the characteristics of this free radical scavenger, further investigation was carried out. Edaravone ameliorated exacerbation of cortical edema induced by a focal ischemia-reperfusion model in rats, suggesting inhibitory effects on oxidative injury to the blood-brain barrier (BBB). Additionally, edaravone also prevented rat cortical edema caused by intracortical AA infusion in which free radical production and subsequent oxidative injury to the BBB are involved. With advances in in vivo measurement technology of oxygen radicals, edaravone was shown to inhibit postischemic increases in .OH production and tissue injury in the penumbral or recirculated area in rat cerebral ischemia models. In clinical studies, edaravone improved the core neurologic deficits, activities of daily living, and functional outcome of stroke patients. Furthermore, a study using proton magnetic resonance spectroscopic techniques showed that edaravone preserved N-acetyl-aspartate in stroke patients, a promising neuronal marker in the brain. Further investigation is essential for a better understanding of free radical-mediated cerebral injury during ischemia followed by recirculation. We hope that edaravone represents a promising neuroprotectant for drug therapy in acute cerebral ischemia.

This paper describes the discovery of a novel free radical scavenger, 3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone, 1), as a potent antioxidant agent against lipid peroxidation. The structure-activity relationship of edaravone indicated that lipophilic substituents were essential to show its lipid peroxidation-inhibitory activity. In vivo studies revealed that edaravone showed brain-protective activity in a transient ischemia model.

Osmotic, sodium and chloride regulations of hemolymph in Hemigrapsus sanguineus were investigated. The crabs exhibited strong hyperosmoregulation in the range of 50-75% SW. Sodium and chloride ions were also well regulated in the same salinity range. The speciffic activity of gill Na++K+-ATPase was higher in the posterior gills than in the anterior gills. In the posterior gills, the Na++K+-ATPase activity showed an increase of 1.5 times with acclimation from 100% SW to 50% SW. Absorption of sodium ion by H. sanguineus in low salinity may be attributed to the function of the posterior gills which have a high level of Na++K+-ATPase activity.

The presence of lithium trifluoromethanesulfonate accelerates the enolate formation from t-butyl δ-hydroxy carboxylates with lithium diethylamide. The reaction of the resulting enolates with ketones or benzaldehyde affords the corresponding α,δ-syn aldol adducts stereoselectively.

The atomic image of 2H-NbSe2 surface was successfully recorded with a scanning tunneling microscope (STM) at room temperature. The trigonal pattern of the image is in good agreement with the results of the X-ray diffraction experiments. The STM apparatus developed here showed resolutions of 0.3 nm in the lateral scale and 0.05 nm in the vertical scale.

A scanning tunneling microscope (STM) with a capability of spectroscopic measurement for operation for 300 K to 1.2 K was constructed. Measurements of the current-voltage characteristics (I-V's) were performed on 2H-NbSe2 and a high-T c superconductor Y-Ba-Cu-O. Spatial variations in the local density of states (LDOS) relevant to the low temperature phases, CDW and superconductivity, were extracted from data statistics.

Anomalously large surface corrugation of 2H-NbSe2crystal was observed by scanning tunneling microscopy (STM). Besides mounds representing the Se atoms, hollow sites and Nb-atom sites clearly appeared as dips and saddle points, respectively. The lateral resolution was proved to be better than 0.2 nm. The large corrugation amplitude was attributed to the effect of atomic force between the tip and the sample.

Langmuir-Blodgett films of cadmium-arachidate have been studied by scanning tunneling microscopy (STM). Substrates of gold and graphite are used to make mono- and bilayer films. The image of the individual molecule cannot be obtained for the films on gold, but the data indicate disturbances on the tunneling current caused by the films. As for the films on graphite, the molecular images with a spacing of 0.4–0.7 nm are recognized in some frames of the variable tunneling current image recorded on videotape. Possible mechanisms of the imaging are discussed.