著者

山下 純一 安本 三治 橋本 貞夫

出版者

公益社団法人日本薬学会

雑誌

Chemical & pharmaceutical bulletin (ISSN:00092363)

巻号頁・発行日

vol.31, no.11, pp.3872-3877, 1983-11-25

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The mechanism of the condensation of 5-fluorouracil and 2-acetoxytetrahydrofuran (3), giving 1-(tetrahydro-2-furyl)-5-fluorouracil, was studied. An equilibrium between 2-acetoxytetrahydrofuran (3) and 2,3-dihydrofuran (4) was observed at 120-170℃ in dimethylformamide. It was found by the use of 1,3-dideuterio-5-fluorouracil that the condensation of 5-fluorouracil with 3 occurred both by direct substitution and by the formation of 4 from 3 followed by addition of the uracil to it. The contribution of the latter path increased with increase of the reaction temperature.

著者

山下 純一 武田 節夫 松本 宏 寺田 忠史 采見 憲男 安本 三治

出版者

公益社団法人日本薬学会

雑誌

Chemical & pharmaceutical bulletin (ISSN:00092363)

巻号頁・発行日

vol.35, no.5, pp.2090-2094, 1987-05-25

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Various O-acyl and N-acyl derivatives of 2'-deoxy-5-trifluoromethyluridine (F_3Thd) were synthesized; namely 5'-O-acyl, 3',5'-di-O-acyl, N^3-acyl, 3',5'-di-O-acetyl-N^3-acyl, 3',5'-di-O-carbamoyl and 3',5'-di-O-ethoxycarbonyl compounds. 5'-O-Acyl derivatives of 2'-deoxy-5-trifluoromethylcytidine were also synthesized. The antitumor activities of these compounds against sarcoma 180 were examined by oral administration to mice. Among the 5'- and 3',5'-diester compounds with aliphatic acids, the 5'-O-hexanoyl compound showed the highest activity. Full protection of the sugar moiety with aroyl or carbamoyl groups considerably decreased the activities, and those of the 3',5'-di-O-m-fluorobenzoyl and 3',5'-di-O-butylcarbamoyl compounds were the smallest. N^3-Benzoyl compounds were slightly more effective than F_3Thd but none of them showed higher activity than the effective O-acyl compounds. In the case of 5'-O-acylates of 2'-deoxy-5-trifluoroniethylcytidine, the 5'-O-benzoyl compound showed the highest activity.

著者

山下 純一 武田 節夫 松本 宏 采見 憲男 安本 三治

出版者

公益社団法人日本薬学会

雑誌

Chem. Pharm. Bull. (ISSN:00092363)

巻号頁・発行日

vol.35, pp.2373-2381, 1987

被引用文献数

1

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Various O-alkoxyalkyl derivatives of 2'-deoxy-5-trifluoroniethyluridine(F_3Thd) were synthesized, and the antitumor activities of the compounds against sarcoma 180 were examined by oral administration to mice. Among the formal-type derivatives, 3',5'-di-O-ethoxymethyl (3), 3',5'-di-O-benzyloxyinethyl (12), 5'-O-benzyloxymethyl (13) and 3'-O-benzyloxymethyl (14) compounds showed high activities, which were six-fold higher than that of F_3Thd itself. Since acetal-type derivatives were unstable under acidic conditions, antitumor testing of the compounds was also carried out with co-administration of sodium bicarbonate. 5 '-O-(1-Ethoxypropyl)-F_3Thd (25) and 5'-O-(1-benz:yloxypropyl)-F_3Thd (37) showed the highest activities among the acetal-type derivatives, but the ED_50 values of the compounds were not lower than those of effective formal-type compounds. These O-alkoxyalkyl derivatives of F_3Thd are resistant to degradation by thymidine phosphorylase and are activated by microsornal drug-metabolizing enzymes after absorption.

著者

山脇 一郎 鈴木 雅博 小川 和男

出版者

公益社団法人日本薬学会

雑誌

Chemical & pharmaceutical bulletin (ISSN:00092363)

巻号頁・発行日

vol.42, no.4, pp.963-971, 1994-04-15

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Piperazinealkanol ester derivatives of indomethacin were prepared and tested for inhibitory activities against 5-lipoxygenase (5-LO) and cyclooxygenase (CO). They inhibited 5-hydroxyeicosatetraenoic acid (5-HETE) formation by the cytosol of guinea pig polymorphonuclear leukocytes and thromboxane B_2 (TXB_2) formation by washed rabit platelet suspension. Of the test compounds, 2-[4-(2-hydroxyethyl)-1-piperazinyl]-1-phenylethyl 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylacetate dimaleate (II-8) was found to be the most active dual inhibitor of 5-LO and CO, and its inhibitory potency was higher than that of 2-[4-(3-hydroxypropyl)-1-piperazinyl]-ethyl [1-(4-chlorobenzoyl)-5-methoxy-2-methyl]-3-indolylacetate (CR-1015) (I), the lead compound.

著者

鈴木 雅博 田中 博道 宮坂 貞

出版者

公益社団法人日本薬学会

雑誌

Chemical & pharmaceutical bulletin (ISSN:00092363)

巻号頁・発行日

vol.35, no.10, pp.4056-4063, 1987-10-25

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Several 5-carbon-substituted 1-β-D-ribofuranosylimidazole-4-carboxamides were synthesized via the direct C-5 lithiation of a protected 4-carboxamide derivative as the key reaction step. Wittig reaction of a 5-formyl derivative was also examined.

著者

神田 博史 徳本 和佳子 坂本 季代恵 藤井 美智子 平井 裕子 山崎 和男 菰田 泰夫 中村 英雄 石原 茂正 内田 勝

出版者

公益社団法人日本薬学会

雑誌

Chemical & pharmaceutical bulletin (ISSN:00092363)

巻号頁・発行日

vol.33, no.4, pp.1367-1374, 1985-04-25

被引用文献数

12

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The MeOH extract of Ganoderma lucidum has an inhibitory action on histamine release from rat mast cells. From the physiologically active fraction of the extract, along with the known triterpenes ganoderic acids A and B, two new triterpenes were isolated and named ganoderic acids C and D. The structures of ganoderic acids C and D were determined to be 3β, 7β, 15α-trihydroxy-11,23-dioxo-5α-lanost-8-en-26-oic acid and 7β-hydroxy-3,11,15,23-tetraoxo-5α-lanost-8-en-26-oic acid respectively. Ganoderic acids C and D were shown to inhibit histamine release from rat mast cells. Quantitative analysis of these triterpenes was performed for the purpose of crude drug quality control.

著者

砂本 順三 岩本 清 上杉 辰顕 小島 一幸 古瀬 一磨

出版者

公益社団法人日本薬学会

雑誌

Chemical & pharmaceutical bulletin (ISSN:00092363)

巻号頁・発行日

vol.32, no.8, pp.2891-2897, 1984-08-25

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To evaluate the spermicidal effect of several nonionic surfactants against human spermatozoa, the physicochemical lysis of liposomal membranes by the surfactants has been investigated. Surfactants employed in this work were menfegol (TS-88), nonoxynol-9 (INP-90), octoxynol-9 (NOP-90), hexadecyltrimethylammonium bromide (CTAB), and sodium dodecylsulfate (SDS). Lysis of liposomes by these spermicidal surfactants was quantitatively followed by monitoring the induced release of carboxyfluorescein (CF) encapsulated in the interior of liposomes. When the liposomes reconstituted with boar spermatozoal lipids and about 31% (by wt.) cholesterol were employed, the sequence in efficiency of the surfactant-induced CF release from the liposomes was significantly correlated with that of efficiency of the surfactants in immobilizing human sperm (p<0.05). On the other hand, when egg lecithin liposomes or the liposomes reconstituted with boar spermatozoal lipids and cholesterol less than 21% (by wt.) were utilized, the sequence in efficiency of CF release from these liposomes coincided with that in the inhibiting effect of the surfactants on the fertilizing ability of sea urchin sperm. These effects were closely correlated with the membrane fluidity as controlled by the cholesterol content or lipid composition. Among menfegol analogues from TS-40 through TS-200,the efficiency in induced CF release from the liposomes showed a maximum at around ten ethylene oxide units length of the hydrophilic moiety in the surfactant. This was also the case for spermicidal effect of the TS-series surfactants. The data obtained are discussed at the molecular level from the viewpoint of the structural characteristics of the surfactants.

著者

Liu Weiping Qing Chen Chen Xizhu YE Qingsong YU Yao HOU Shuqian

出版者

公益社団法人日本薬学会

雑誌

Chemical & pharmaceutical bulletin (ISSN:00092363)

巻号頁・発行日

vol.56, no.5, pp.659-662, 2008-05-01

被引用文献数

1 6

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New JM118 (active form of satraplatin) analogues with N-cyclohexyl-1,3-propanediamine (N-chpda) as the carrier, cis-[Pt(N-chpda)X_2] (X_2=2Cl^- (1), oxalate (2), malonate (3), 1,1-cyclobutanedicarboxylate (CBDCA) (3), and 3-hydroxy-1,1-cyclobutanedicarboxylate(HO-CBDCA) (4)), have been synthesized and characterized by elemental analysis and spectroscopic data along with X-ray crystal structure for a representative compound cis-[Pt(N-chpda)Cl_2]. The complexes have also been evaluated for their in vitro anticancer activity. All these analytical data are in good agreement with the structures of the desired compounds. The Pt(II) is in a square planar environment and is coordinated by a chelating N-chpda ligand and 2Cl^- in cis position, and there are two crystallo-graphically independent cis-[Pt(N-chpda)Cl_2] molecules linked together by intermolecular N-H…Cl hydrogen bonds. Compounds 1 and 2 are very active against human lung cancer cell line (AGZY) and human lymphocytic leukemia cell line (Raji), and are much more active than carboplatin. Platinum(II) complexes with N-cyclohexyl-1,3-propanediamine is an alternative choice for mixed ammine/aminoplatinum anticancer drugs.

著者

松本 仁 磯部 明彦

出版者

公益社団法人日本薬学会

雑誌

Chemical & pharmaceutical bulletin (ISSN:00092363)

巻号頁・発行日

vol.29, no.3, pp.603-608, 1981-03-25

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The emission spectra and the fluorescence quantum yields of psoralens were measured in various solvents. We found that these compounds show a large Stokes shift, which can be explained in terms of intermolecular charge transfer interaction between a solute molecule and a solvent molecule in an excited singlet state. Psoralens have a larger fluorescence quantum yield in hydroxylic solvents than in non-hydroxylic solvents. These were in the following order : TMP&ap;5-MOP>PS&ap;8-MOP&ap;8-iso-AOP. We postulate that the fluorescence quantum yield is increased by the hydrogen bonding between a solute molecule and a solvent molecule in an excited singlet state. In addition, the fluorescence efficiency was enhanced by the presence of an electron-donating substituent group. The peak wavelengths of the phosphorescence spectra were little affected by the different solvents.

著者

横澤 隆子 金井 久美子 岳藤 美知子 大浦 彦吉

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.24, no.12, pp.3202-3204, 1976-12-25 (Released:2008-03-31)

被引用文献数

1 2

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Investigations were carried out to determine whether or not a decreasing action of hepatic glycogen content in rats by ginseng extract is due to its main constituent, saponin. The experimental results suggested that ginseng saponin decreases the glycogen stores, but the degree of its effect is regulated by the nutritional status of rats.

著者

Akihiro Ito Lei Wang Ryotaro Notomi Shigeki Sasaki Yosuke Taniguchi

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.72, no.1, pp.16-20, 2024-01-01 (Released:2024-01-01)

参考文献数

24

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Triplex DNA formation has generated much interest as a genomic targeting tool that directly targets duplex DNA. However, fundamental limitations in the base pairs of target duplex DNA sequences that can form stable triplex DNA have limited the application. Recently, we have reported on the recognition of CG and 5mCG base pairs by artificial nucleic acid derivatives with a 2′-deoxynebularine skeleton. Therefore, we attempted to explore the basic skeleton that is important for the development of new artificial nucleic acids allowing for the recognition of TA base pairs. In this study, we focused on a benzimidazole skeleton and introduced a hydroxyl group to enable one-point hydrogen bonding. We have synthesized artificial nucleoside analogues with hydroxyl group on the benzimidazole and incorporated their amidite derivatives into triplex forming oligonucleotides (TFOs). The gel shift assay was performed to evaluate the triplex DNA formation ability of synthesized TFOs, and TFOs containing hydroxybenzimidazole were successfully recognized TA base pairs for all four different sequences. Moreover, compared to the results for the TFOs containing benzimidazole, which suggested hydrogen bonding formation at the hydroxyl group. Therefore, hydroxybenzimidazole would be an important artificial nucleic acid skeleton for TA base pair recognition.

著者

Takashi Hasegawa Kenji Tsukigawa Kindness Commey Mina Sakuragi Shuhei Imoto Kazuaki Taguchi Koji Nishi Masaki Otagiri Keishi Yamasaki

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.72, no.1, pp.21-27, 2024-01-01 (Released:2024-01-01)

参考文献数

28

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Pirarubicin (THP) shows more rapid intracellular uptake, more effective antitumor activity, and less cardiac toxicity, compared to doxorubicin. However, THP is distributed to both tumor and normal tissues indiscriminately. This study aimed to develop a nanosuspension to deliver THP to tumor tissues more efficiently. Fatty-acid-modified THPs (FA-THPs; octanoic acid, dodecanoic acid, palmitic acid-THPs) were synthesized to increase the hydrophobicity of THP. Nanosuspensions of these FA-THPs were then prepared using an antisolvent precipitation technique. Among the FA-THPs, the most efficiently drug-loaded nanosuspension was obtained from palmitic acid-THP (pal-THP) using an aqueous antisolvent containing bovine serum albumin as a stabilizer. The pal-THP nanoparticles in the nanosuspension were confirmed to be of optimal size (100–125 nm) for delivery to tumor tissues using dynamic light scattering and transmission electron microscopy. The pal-THP nanosuspension showed cytotoxicity in colon 26 cells. The nanosuspension was shown to disintegrate in the presence of surfactants such as lecithin, liberating pal-THP, which was converted to free THP in acidic media. It is therefore proposed that pal-THP nanoparticles that reach tumor cells after intravenous administration would exert antitumor effect by liberating pal-THP (i.e., disintegration of nanoparticles by the interaction with cell membrane), followed by the release of free THP in the acidic milieu of tumor cells. These findings indicate that FA-THP nanosuspensions, particularly pal-THP nanosuspension, hold promise as a candidate for cancer treatment. However, further in vivo studies are necessary.

著者

Sabrina Dahlizar Mika Futaki Akie Okada Wesam Radhi Kadhum Hiroaki Todo Kenji Sugibayashi

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.66, no.3, pp.327-333, 2018-03-01 (Released:2018-03-01)

参考文献数

24

被引用文献数

10 11

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Palmitoyl-glycine-histidine (Pal-GH) is a new low molecular weight gelling agent. It exhibits thixotropic behavior, low viscosity, and high dissolving properties for a wide range of hydrophilic to lipophilic drugs. Orally administered ivermectin (IVM) is used to treat scabies. However, this treatment is associated with well-known side effects, thus a study is awaited to search for alternative routes of administration. Although a topical formulation of IVM could be a candidate, it requires whole body application except the head and face for several hours on a daily basis. Therefore, in this study, we prepared a gel spray formulation containing IVM as an approach for application to large skin areas with a single spray application without further contact with the applied formulation. Pal-GH gel spray formulations were prepared from its aqueous solution by a heating and cooling method. Rheological behavior and physical appearance (spraying, spreading ability, volume of spraying, and homogeneity) of the prepared formulations were evaluated. Pal-GH gel with propylene glycol demonstrated impressive rheological properties (typical thixotropic behavior) with high hysteresis area among all the tested Pal-GH gels and spreading ability. The obtained IVM concentration in the skin after topical application of 0.1% IVM-containing Pal-GH formulation onto hairless rats was much higher than the reported therapeutic concentration obtained from oral administration in humans. These results suggested that topical application of IVM using a Pal-GH gel spray formulation could be an alternative to the conventional oral forms for the scabies treatment.

著者

Kazunori Miwa Yan Guo Masayuki Hata Yoshinori Hirano Norio Yamamoto Tyuji Hoshino

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.71, no.12, pp.897-905, 2023-12-01 (Released:2023-12-01)

参考文献数

40

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Virtual screening with high-performance computers is a powerful and cost-effective technique in drug discovery. A chemical database is searched to find candidate compounds firmly bound to a target protein, judging from the binding poses and/or binding scores. The severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) infectious disease has spread worldwide for the last three years, causing severe slumps in economic and social activities. SARS-Cov-2 has two viral proteases: 3-chymotrypsin-like (3CL) and papain-like (PL) protease. While approved drugs have already been released for the 3CL protease, no approved agent is available for PL protease. In this work, we carried out in silico screening for the PL protease inhibitors, combining docking simulation and molecular mechanics calculation. Docking simulations were applied to 8,820 molecules in a chemical database of approved and investigational compounds. Based on the binding poses generated by the docking simulations, molecular mechanics calculations were performed to optimize the binding structures and to obtain the binding scores. Based on the binding scores, 57 compounds were selected for in vitro assay of the inhibitory activity. Five inhibitory compounds were identified from the in vitro measurement. The predicted binding structures of the identified five compounds were examined, and the significant interaction between the individual compound and the protease catalytic site was clarified. This work demonstrates that computational virtual screening by combining docking simulation with molecular mechanics calculation is effective for searching candidate compounds in drug discovery.

著者

Shota Oyama Mao Tomita Moeka Hata Yu Mikame Tsuyoshi Yamamoto Eishi Ashihara Asako Yamayoshi

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.71, no.11, pp.819-823, 2023-11-01 (Released:2023-11-01)

参考文献数

22

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Exosomes are a type of extracellular vesicles that contain diverse molecules and are present in our body fluids. They play a crucial role in transporting materials and transmitting signals between cells. Currently, there have been numerous reports on the use of exosomes in drug delivery systems (DDS). However, most existing methods for utilizing exosomes in DDS require the isolation and purification of exosomes, which raises concerns about yield and potential damage to the exosomes. Recently, we have developed a novel DDS called “ExomiR-Tracker” that harnesses exosomes without the need for isolation and purification. This system aims to deliver nucleic acid drugs effectively. ExomiR-Tracker consists of an anti-exosome antibody equipped with nona-D-arginines (9 mer) and nucleic acid drugs which have complementary sequence of target microRNA (anti-miR). In this study, we modified ExomiR-Tracker by incorporating branched nona-D-arginines (9 + 9 mer) molecules (referred to as Branch ExomiR-Tracker) and evaluated its efficacy in lung adenocarcinoma cells (A549 cells). The improved complex formation ability and enhanced cellular uptake of anti-miR, demonstrated by our findings, highlight the advantages of incorporating branched oligoarginine peptides into the ExomiR-Tracker platform. These results represent significant progress in revealing the effectiveness of Branch ExomiR-Tracker against adhesive cancer cells, which has not been shown to be effective with the conventional Linear ExomiR-Tracker.

著者

Lin-jiao Wang Wei Xi Xiao-lan Yuan Xiao-hua Yang

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

pp.c22-00843, (Released:2023-10-03)

参考文献数

31

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Dapagliflozin (DAPA), sodium-glucose co-transporter 2 (SGLT-2) inhibitor, is used to treat Type 2 diabetes. In this study, a highly sensitive and selective analytical method based on ultra-high performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS) was established and validated for the determination of DAPA in rat plasma. The separation of DAPA and internal standard (DAPA-d5) were performed on a reversed-phase ACQUITY UPLC® BEH C18 column (100×3.0 mm, 1.7 µm). The mobile phase is composed of 0.1% formic acid in water (solvent A) and methanol (solvent B) in gradient elution. Under the negative ion mode, full MS/dd-MS2 was adopted to collect data via Q-Orbitrap. DAPA was effectively separated from matrix backgrounds within 10 min, and DAPA in plasma showed a good linear relationship in the range of 10-10000 µg/L. The determination coefficient (R2) was 0.9987, and the lower limit of quantification (LLOQ) was 10 µg/L. The precision and accuracy were all less than 10%, and the extraction recovery of DAPA was 86.16%-96.06% from plasma. This study offered an efficient separation and quantification method for DAPA. The improved and validated method succeeded in evaluating the pharmacokinetics of DAPA in rat plasma samples after a single oral administration of 1 mg/kg.

著者

Shohei Nakamura Nanami Ito Ayumi Sakurada Takatoshi Sakamoto

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.71, no.9, pp.687-694, 2023-09-01 (Released:2023-09-01)

参考文献数

43

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Lactose is an excipient used extensively for bulking, diluting, and molding active pharmaceutical ingredients in tablet manufacturing. Particularly, granulated lactose (GL) intended for direct powder compression has distinct properties due to differences in manufacturing methods. It contributes to handling blended powders for tableting and tablet quality. In this study, we aimed to compare the functions of different forms of GL added as excipients during direct powder compression on the tablet properties and the effect of magnesium stearate (Mg-S) used as a lubricant on each type of GL. Different GL types obtained using different manufacturing methods (agitated granulation, GL-AG; spray-dried granulation, GL-SD; fluidized bed granulation, GL-FB) were blended with maize starch, low-substituted hydroxypropyl cellulose, and paracetamol in a V-type blender for 10 min. Mg-S was added at varying amounts (0.1, 1.0, and 2.0%) and blending times (5, 10, and 30 min) for the nine types of blended powders for tableting formulation. The powders were tableted, and the tablets were evaluated for weight and drug loading variations, tensile strength, friability, and disintegration time. When tablets with the same blending conditions were compared, the tensile strength and disintegration time were in the order of GL-FB > GL-SD > GL-AG. For each GL, we analyzed the effects of changes in the added amount of Mg-S and blending time using contour plots, evaluated the effects of blending conditions on tablet properties, and determined the target tablet properties. We investigated the optimization of the lubricant blending conditions to obtain suitable tablets.

著者

Shota Kawai Shunsuke Takashima Masafumi Ando Sayaka Shintaku Shigemitsu Takeda Kazuya Otake Yuma Ito Masaki Fukui Megumi Yamamoto Yoshimichi Shoji Hiroaki Shirahase Tatsuya Kitao

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.71, no.9, pp.701-716, 2023-09-01 (Released:2023-09-01)

参考文献数

27

被引用文献数

1

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The readthrough mechanism, which skips the premature termination codon and restores the biosynthesis of the defective enzyme, is an emerging therapeutic tactic for nonsense mutation-related diseases, such as Hurler syndrome, a type of mucopolysaccharidosis. In the present study, novel triaryl derivatives were synthesized and their readthrough-inducing activities were evaluated by a luciferase reporter assay with a partial α-L-iduronidase (IDUA) DNA sequence containing the Q70X nonsense mutation found in Hurler syndrome and by measuring the enzyme activity of IDUA knockout cells transfected with the mutant IDUA gene. KY-516, a representative compound in which the meta position carboxyl group of the left ring of the clinically used ataluren was converted to the para position sulfamoylamino group, the central ring to triazole, and the right ring to cyanobenzene, exhibited the most potent readthrough-inducing activity in the Q70X/luciferase reporter assay. In Q70X mutant IDUA transgenic cells, KY-516 significantly increased enzyme activity at 0.1 µM. After the oral administration of KY-516 (10 mg/kg), the highest plasma concentration of KY-516 was above 5 µM in rats. These results indicate that KY-516, a novel triaryl derivative, exhibits potent readthrough-inducing activity and has potential as a therapeutic agent for Hurler syndrome.

著者

Rie Ito Chisa Takemura Hiroshi Akiyama Koichi Saito

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.71, no.4, pp.312-317, 2023-04-01 (Released:2023-04-01)

参考文献数

15

被引用文献数

1

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The degradation behavior of three benzodiazepines (BZPs)—lormetazepam (LMZ), lorazepam, and oxazepam—with hydroxy groups on the diazepine ring in artificial gastric juice and the effect of storage pH conditions on drug degradability were monitored using an LC/photodiode array detector (PDA) to estimate their pharmacokinetics in the stomach. Although the three BZPs degraded in artificial gastric juice, none could be restored, despite increasing the storage pH, implying that the degradation reaction was irreversible. As for LMZ, we discussed the physicochemical parameters, such as the activation energy and activation entropy involved in the degradation reaction as well as the reaction kinetics; one of the degradation products was isolated and purified for structural analysis. In the LMZ degradation experiment, peaks corresponding to degradation products, (A) and (B), were detected through the LC/PDA measurements. Regarding the degradation behavior, we hypothesized that LMZ was degraded into (B) via (A), where (A) was an intermediate and (B) was the final product. Although the isolation of degradation product (A) was challenging, degradation product (B) could be isolated and was confirmed to be “methanone, [5-chloro-2-(methylamino)phenyl](2-chlorophenyl)-” based on structure determination using various instrumental analyses. The compound exhibited axis asymmetry as determined using single-crystal X-ray structure analysis. Because the formation of degradation product (B) was irreversible, it would be prudent to target the final degradation product (B) and LMZ for identification when detecting LMZ in human stomach contents, such as during forensic dissection.

著者

Shota Tokunaga Chie Uchikoshi Kyu Hayashi Hironori Suzuki Masataka Ito Shuji Noguchi

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.71, no.8, pp.633-640, 2023-08-01 (Released:2023-08-01)

参考文献数

45

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Nobiletin (NOB) is a flavonoid with attractive pharmaceutical characteristics, including anti-Alzheimer’s, anti-inflammation, and anti-cancer properties, but it has low solubility in water, resulting in reduced bioavailability. Its solubility must be improved to develop NOB as a drug. Cocrystal engineering can change the physicochemical properties of an active pharmaceutical ingredient and generate remarkable drug candidates that are superior in drug formulation. In this report, extensive co-crystal screening of NOBs with 31 cocrystal formers (coformers) with various functional groups was carried out by the liquid-assisted grinding method. As a result, four cocrystals (NOB with urea (URE), oxalic acid, gallic acid and salicylic acid) and one solvate crystal (NOB with formic acid (FOR)) were found. Powder X-ray diffraction and thermal analysis revealed the unique crystal morphology of all the obtained samples. In addition, the crystal structures of two of them (NOB-URE and NOB-FOR) were determined by single crystal X-ray diffraction. The results revealed that NOB-URE and NOB-FOR are new cocrystals or solvate crystals consisting of molar ratios of 1 : 2 and 1 : 0.73, respectively. In NOB-URE, we could observe a transient increase in solubility due to supersaturation, suggesting that URE is one of the better coformers of NOB.