著者

Takashi Motoyaji

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.68, no.3, pp.191-193, 2020-03-01 (Released:2020-03-01)

参考文献数

16

被引用文献数

15

---

Affinity selection (AS)-MS is a label-free binding assay technology for the analysis of interactions between targets and small drug molecules, which does not require modification of targets or compounds. AS-MS technology has been used in drug discovery research for more than 10 years, and is currently one of the most important affinity-based screening techniques. As such, it may be the driving force for novel small molecule drug discovery. This review introduces the principles of AS-MS technology and its use in high-throughput screening (HTS), then discusses strategies for its use in drug discovery and its application in target identification.

著者

Katsuhiko Sekimata Tomohiro Sato Naoki Sakai

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.68, no.3, pp.194-200, 2020-03-01 (Released:2020-03-01)

参考文献数

70

被引用文献数

9

---

Fibrodysplasia ossificans progressiva (FOP) and diffuse intrinsic pontine glioma (DIPG) are diseases that typically manifest in childhood and are associated with severely reduced life expectancy. However, there are currently no effective therapies for these diseases, which remain incurable. Activin receptor-like kinase-2 (ALK2), encoded by the ACVR1 gene, is a bone morphogenetic protein (BMP) type-I receptor subtype that plays an important physiological role in the development of bones, muscles, brain, and other organs. Constitutively active mutants of ALK2 have been identified as causative of FOP and involved in the tumorigenesis of DIPG owing to abnormal activation of BMP signaling, and therefore have emerged as promising treatment targets. Here, we describe these two diseases, along with the link to ALK2 signal transduction, and highlight potential ALK2 inhibitors that are under development to offer new hope for patients with FOP and DIPG.

著者

Atsushi Yoshimori Enzo Kawasaki Chisato Kanai Tomohiko Tasaka

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.68, no.3, pp.227-233, 2020-03-01 (Released:2020-03-01)

参考文献数

38

被引用文献数

15

---

The goal of drug design is to discover molecular structures that have suitable pharmacological properties in vast chemical space. In recent years, the use of deep generative models (DGMs) is getting a lot of attention as an effective method of generating new molecules with desired properties. However, most of the properties do not have three-dimensional (3D) information, such as shape and pharmacophore. In drug discovery, pharmacophores are valuable clues in finding active compounds. In this study, we propose a computational strategy based on deep reinforcement learning for generating molecular structures with a desired pharmacophore. In addition, to extract selective molecules against a target protein, chemical genomics-based virtual screening (CGBVS) is used as post-processing method of deep reinforcement learning. As an example study, we have employed this strategy to generate molecular structures of selective TIE2 inhibitors. This strategy can be adopted into general use for generating selective molecules with a desired pharmacophore.

著者

Masao Toyota Takuji Shimamura Hikari Ishii Matt Renner John Braggins Yoshinori Asakawa

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.50, no.10, pp.1390-1392, 2002 (Released:2002-10-01)

参考文献数

5

被引用文献数

26 74

---

The ether extract of the New Zealand liverwort Radula marginata afforded a new cannabinoid type bibenzyl compound named perrottetinenic acid, and two new bibenzyls, together with a known cannabinoid, perrottetinene. Their structures were established by two dimensional (2D) NMR spectral data. The structure of perrottetinenic acid was a similar to that of Δ1-tetrahydrocannabinol, a known hallucinogen. Cannabinoid type bibenzyls have been isolated from liverwort Radula perrottetii, though have not previously been reported from the liverwort R. marginata.

著者

Arno Hazekamp Young Hae Choi Robert Verpoorte

出版者

公益社団法人日本薬学会

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.52, no.6, pp.718-721, 2004 (Released:2004-06-01)

参考文献数

18

被引用文献数

29 76

---

A 1H-NMR method has been developed for the quantitative analysis of pure cannabinoids and for cannabinoids present in Cannabis sativa plant material without any chromatographic purification. The experiment was performed by the analysis of singlets in the range of δ 4.0—7.0 in the 1H-NMR spectrum, in which distinguishable signals of each cannabinoid are shown. Quantitation was performed by calculating the relative ratio of the peak area of selected proton signals of the target compounds to the known amount of the internal standard, anthracene. For this method no reference compounds are needed. It allows rapid and simple quantitation of cannabinoids with a final analysis time of only 5 min without the need for a pre-purification step.

著者

Kohei Tsuji Takuya Kobayakawa Takahiro Ishii Nobuyo Higashi-Kuwata Chika Azuma Kouki Shinohara Yutaro Miura Kenichi Yamamoto Soshi Nishimura Shin-ichiro Hattori Haydar Bulut Hiroaki Mitsuya Hirokazu Tamamura

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.879-886, 2023-12-01 (Released:2023-12-01)

参考文献数

53

---

In the development of anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) drugs, its main protease (Mpro), which is an essential enzyme for viral replication, is a promising target. To date, the Mpro inhibitors, nirmatrelvir and ensitrelvir, have been clinically developed by Pfizer Inc. and Shionogi & Co., Ltd., respectively, as orally administrable drugs to treat coronavirus disease of 2019 (COVID-19). We have also developed several potent inhibitors of SARS-CoV-2 Mpro that include compounds 4, 5, TKB245 (6), and TKB248 (7), which possesses a 4-fluorobenzothiazole ketone moiety as a reactive warhead. In compounds 5 and TKB248 (7) we have also found that replacement of the P1-P2 amide of compounds 4 and TKB245 (6) with the corresponding thioamide improved their pharmacokinetics (PK) profile in mice. Here, we report the design, synthesis and evaluation of SARS-CoV-2 Mpro inhibitors with replacement of a digestible amide bond by surrogates (9–11, 33, and 34) and introduction of fluorine atoms in a metabolically reactive methyl group on the indole moiety (8). As the results, these compounds showed comparable or less potency compared to the corresponding parent compounds, YH-53/5h (2) and 4. These results should provide useful information for further development of Mpro inhibitors.

著者

Akira Otaka

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.70, no.11, pp.748-764, 2022-11-01 (Released:2022-11-01)

参考文献数

111

被引用文献数

1

---

Diverse naturally occurring events relevant to proteins, including processing and post-translational modification, provide significant clues enabling advances in peptide/protein chemistry. Our motivation to synthesize large proteins prompted us to seek scientific bases utilized in synthetic experiments on the intein-mediated protein processing system. This account describes peptide/protein thioester-producing protocols whose design is based on acyl transfer reactions observed in the intein system, and the development of the stimulus-responsive amide cleavage and its application to the modulation of peptide function. Finally, several findings derived from nature-inspired research efforts, including peptide mimetic synthesis and S-protected cysteine chemistry, are described.

著者

Atsushi Yamamoto Ko Nakamura Kazuhito Furukawa Yukari Konishi Takashi Ogino Kunihiko Higashiura Hisashi Yago Kaoru Okamoto Masanori Otsuka

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.50, no.1, pp.47-52, 2002 (Released:2002-03-19)

参考文献数

18

被引用文献数

21 32

---

To find new tachykinin NK1 receptor antagonists from natural sources, we examined the tachykinin antagonist activity in the extracts of approximately 200 species of plants by the use of isolated guinea pig ileum. As a result, we discovered a novel and potent NK1 receptor antagonist in the extract of dried flowers of Matricaria chamomilla L. (chamomile). The structure of the antagonist was established as N1, N5, N10, N14-tetrakis[3-(4-hydroxyphenyl)-2-propenoyl]-1, 5, 10, 14-tetraazatetradecane (tetracoumaroyl spermine, 1a). The Ki values of 1a, estimated from the inhibitory action on the substance P (SP)-induced contraction of the guinea pig ileum and the inhibition of the binding of [3H][Sar9, Met(O2)11]SP to human NK1 receptors, were 21.9 nM and 3.3 nM, respectively. 1a is the first potent NK1 receptor antagonist from natural sources and it has a unique structure of a polyacylated spermine. 1a was concentrated in pollen of Matricaria chamomilla L. and was also found in the extracts of flowers of other four species of Compositae. In addition, we found N1, N5, N10-tris[3-(4-hydroxyphenyl)-2-propenoyl]-1, 5, 10, 14-tetraazatetradecane (2) as a new compound in the extract of flowers of Matricaria chamomilla L., which did not exhibit any tachykinin antagonist activity. A number of related compounds were synthesized, and the structure–activity relationship was studied.

著者

Shiori Takashina Miki Takahashi Koji Morimoto Koichi Inoue

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.70, no.2, pp.169-174, 2022-02-01 (Released:2022-02-01)

参考文献数

17

被引用文献数

5

---

Cannabidiol (CBD), a major non-psychoactive cannabinoid, has a lot of attention due to its potential relaxing properties and led the trend in commercial CBD aroma/oral hemp seed oil from the Japanese market. In this study, a routine assay for evaluating CBD oil samples was performed using LC coupled with tandem mass spectrometry (LC-MS/MS) and was used to apply the convertible tetrahydrocannabinol (THC) in acetic acid conditions. Based on the electrospray positive ion mode, the detection of cannabidiolic acid (CBDA; m/z 359 > 219), cannabigerolic acid (CBGA; m/z 361 > 343), cannabigerol (CBG; m/z 317 > 193), CBD (m/z 315 > 193), THC (m/z 315 > 193) and cannabinol (CBN; m/z 311 > 223) was performed by satisfying separation with high density of C18 column. Oil samples (50 mg) were diluted with isopropanol (5 mL), to which stable isotope internal standards were added by dilution with methanol/water (50/50), and accuracy rates ranged from 97.8 to 102.2%. This method was used to evaluate the CBD oil products (5 kinds) from the Japanese market. Our survey found obvious counterfeit (non-detectable CBD) CBD oil from Japanese market. Following that, we investigated the conversion of THC in CBD oil samples in simple conditions such as 10% acetic acid and 70 °C for 6 h and discovered that converts THC proportions are approximately 5% ((THC content/CBD content) × 100) and <1.0%. Thus, our developed LC-MS/MS assay could be applied to monitor the CBD concentration and convertible THC from CBD oil.

著者

Mariko Kimoto Toshiyasu Sakane Hidemasa Katsumi Akira Yamamoto

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.70, no.2, pp.138-145, 2022-02-01 (Released:2022-02-01)

参考文献数

25

被引用文献数

1

---

The dissolution behaviors of base excipients from sustained-release formulations have been investigated using various methodologies. However, the dissolution of polymers has not been fully evaluated because differences between formulations are still verified only by the release of active pharmaceutical ingredients (APIs). In our previous study, we proposed a quick and simultaneous analysis of dissolved APIs and water-soluble polymers by ultra HPLC using charged aerosol and photodiode array detectors. The purpose of this study was to verify whether the analysis system could be adapted to other water-soluble polymers. Dissolution tests were conducted using matrix model tablets prepared from three polymers and three APIs (propranolol, ranitidine, and cilostazol) with different solubilities. The dissolution profiles of the polymers and APIs were determined using the proposed analysis system and compared. The results clarified differences in the dissolution behaviors of the APIs and polymers. The polymers, especially hydroxypropyl cellulose, exhibited the dissolution properties characteristic of each model formulation. Propranolol and ranitidine showed the diffusion type, while cilostazol showed the erosion type release mechanism due to their different solubilities. The release of cilostazol was delayed in all models compared to the polymer, which may be due to the aggregation of cilostazol in the gel layer. This analytical method can be used to study the dissolution behavior (diffusion or erosion) of APIs from matrix tablets containing various polymers. This method will provide useful information on release control, which will make it easier and more efficient to design appropriate formulations and analyze the release mechanisms.

著者

Nanako Nakashima Jukiya Sakamoto Kenta Rakumitsu Mariko Kitajima Lia Dewi Juliawaty Hayato Ishikawa

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.70, no.2, pp.187-191, 2022-02-01 (Released:2022-02-01)

参考文献数

23

被引用文献数

5

---

A new pentacyclic monoterpenoid indole alkaloid glycoside named secorubenine (1) was isolated from the heartwood of Adina rubescens, collected in Indonesia. The structure was elucidated by spectroscopic analysis and chemical modification of isolated secorubenine (1). The bioinspired enantioselective total synthesis of 1 was accomplished in 12 steps, whereafter its structure was determined and the absolute stereochemistry was confirmed.

著者

三宅 昭夫 岡 良和 万木 庄次郎

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.23, no.7, pp.1500-1504, 1975-07-25 (Released:2008-03-31)

被引用文献数

1 6

---

Photochemical reactions of tetraazanaphthalene derivatives, I, II, and III, with alcohols and cyclic ethers in the presence of photosensitizer resulted in selective addition at the 3, 4 C=N bond to give substituted-3, 4-dihydro derivatives. Potential diuretic activity was shown by many of the obtained compounds.

著者

Hirotomo Moriwaki Yu-Shi Tian Norihito Kawashita Tatsuya Takagi

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.67, no.5, pp.426-432, 2019-05-01 (Released:2019-05-01)

参考文献数

22

被引用文献数

3

---

Quantitative structure–activity relationship (QSAR) techniques, especially those that possess three-dimensional attributes, such as the comparative molecular field analysis (CoMFA), are frequently used in modern-day drug design and other related research domains. However, the requirement for accurate alignment of compounds in CoMFA increases the difficulties encountered in its use. This has led to the development of several techniques—such as VolSurf, Grid-independent descriptors (GRIND), and Anchor-GRIND—which do not require such an alignment. We propose a technique to construct the prediction model that uses molecular interaction field grid potentials as inputs to convolutional neural network. The proposed model has been found to demonstrate higher accuracy compared to the conventional descriptor-based QSAR models as well as Anchor-GRIND techniques. In addition, the method is target independent, and is capable of providing useful information regarding the importance of individual atoms constituting the compounds contained in the chemical dataset used in the proposed analysis. In view of these advantages, the proposed technique is expected to find wide applications in future drug-design operations.

著者

Jun Shimokawa

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.2, pp.105-115, 2018-02-01 (Released:2018-02-01)

参考文献数

153

被引用文献数

4

---

The divergent total syntheses of three types of heteropolycyclic natural products, namely gelsedine-type alkaloids, amathaspiramide alkaloids, and erythrina alkaloids, are outlined. A strategy involving a late-stage pluripotent common synthetic intermediate prepared via original and innovative transformations was employed. A brief description of the philosophy and criteria for choosing the synthetic targets and common synthetic precursors, as well as details regarding the development of the overall synthetic schemes from a common intermediate are discussed.

著者

Yo Muraki Midori Yamasaki Hirohisa Takeuchi Kimio Tohyama Noriyasu Sano Takanori Matsuo

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

pp.c17-00811, (Released:2018-01-06)

参考文献数

36

被引用文献数

6

---

Pulmonary hypertension (PH) is a life-threatening lung disease. Despite the availability of several approved drugs, the development of a new treatment method is needed because of poor prognosis. Tissue selective drug delivery systems can avoid the adverse effects of current therapy and enhance efficacy. We evaluated the possibility of delivering drugs to the lungs of a PH rat model using fluorescence dye-labeled nanosized liposomes. To evaluate the tissue distribution following systemic exposure, fluorescent dye-labeled, 40-180 nm liposomes with and without polyethylene glycol (PEG) were intravenously administered to a monocrotaline-induced PH (MCT) rat model and tissue fluorescence was measured. Fluorescent dye-containing liposomes were intratracheally administered to the MCT model to evaluate the distribution of the liposome-encapsulated compound following local administration to reduce systemic exposure. The lung vascular permeability, plasma concentration of surfactant protein (SP)-D, lung reactive oxygen species (ROS) production, and macrophage marker gene cluster of differentiation (CD68) expression were measured. PEG and 80-nm liposome accumulation in the lung was elevated in the MCT model compared to that in normal rats. The intratracheally administered liposomes were delivered selectively to the lungs of the MCT model. The lung vascular permeability, plasma SP-D concentration, and CD68 expression were significantly elevated in the lungs of the MCT model, and were all significantly and positively correlated to liposome lung accumulation. Liposomes can accumulate in the lungs of an MCT model by enhancing vascular permeability by the inflammatory response. Therefore, drug encapsulation in liposomes could be an effective method of drug delivery in patients with PH.

著者

兼松 顯 内藤 良 下東 康幸 大野 素徳 小笠原 富夫 黒野 昌庸 八木 國夫

出版者

公益社団法人日本薬学会

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.38, no.5, pp.1438-1440, 1990-05-25 (Released:2008-03-31)

参考文献数

6

被引用文献数

7 14

---

An S-activated sulfhydrylmorphine derivative was synthesized, and its linking to the μ-opioid receptor through a disulfide bond was demonstrated.

著者

Shinji Katsura Nobuo Yamada Atsushi Nakashima Sumihiro Shiraishi Mihoko Gunji Takayuki Furuishi Tomohiro Endo Haruhisa Ueda Etsuo Yonemochi

出版者

公益社団法人日本薬学会

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.65, no.4, pp.373-380, 2017-04-01 (Released:2017-04-01)

参考文献数

14

被引用文献数

2

---

We observed that uncoated furosemide tablets turned yellow in a light-shielded automatic packaging machine and discoloration of the furosemide tablets was heterogeneity and occurred on the surface of the tablets only. The machine was equipped with an internal blower to maintain a constant temperature. Therefore, we investigated the effect of air flow on the discoloration of the furosemide tablets using a blower in a dark environment. The color difference (ΔE) of the furosemide tablets increased linearly as the blowing time increased. We performed structural analysis of the yellow compound in the furosemide tablets by LC-MS and identified the compound as a hydrolysate of furosemide. This suggested that furosemide hydrolysis was accelerated by the air flow. The furosemide tablets were prepared with the most stable furosemide polymorph, form I. X-Ray powder diffractometry and IR spectroscopy showed that during tablet preparation, no crystal transition occurred to an unstable furosemide polymorph. Furthermore, IR spectroscopy showed that the crystal form of furosemide in the yellow portion of the tablets was form I. To elucidate the factors producing the discoloration, we investigated the effect of humidity and atmosphere (air, oxygen, and nitrogen) on the discoloration of the furosemide tablets. The results suggested that the discoloration of the furosemide tablets was accelerated by oxidation, although humidity did not affect the hydrolysis. Therefore, we concluded that the discoloration of the furosemide tablets in the automatic packing machine was caused by acceleration of oxidative degradation by air flow.

著者

Makoto Ozaki Motoshi Shimotsuma Takefumi Kuranaga Hideaki Kakeya Tsunehisa Hirose

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

pp.c23-00439, (Released:2023-08-24)

参考文献数

34

被引用文献数

1

---

D-Amino acids, which are present in small amounts in living organisms, are responsible for a variety of physiological functions. Some bioactive/biomolecular peptides also contain D-amino acids in their sequences; such peptides express different functions than peptides composed only of L-form amino acids. Among the 20 amino acids that make up proteins, threonine (Thr) and isoleucine (Ile) have two chiral carbons and thus have two enantiomers and diastereomers. These stereoisomers have been previously analyzed through high-performance liquid chromatography using chiral columns or chiral resolution labeling reagents. However, the separation and identification of these stereoisomers are highly laborious and complicated. Herein, we propose an analytical method for the separation and identification of Ile stereoisomers through liquid chromatography–mass spectrometry using an original chiral resolution labeling reagent, 1-fluoro-2,4-dinitrophenyl-5-L-valine-N,N-dimethylethylenediamine-amide (L-FDVDA) and a PBr column packed with pentabromobenzyl-modified silica gel. Twenty DL-amino acids including Thr stereoisomers (41 amino acids including glycine) were separated and identified using C18 column. Ile stereoisomers could be separated using not a C18 column but a PBr column. Additionally, we showed that peptides containing Thr and Ile stereoisomers can be accurately detected through labeling with L-FDVDA.

著者

Yusuke Imayoshi Shuji Ohsaki Hideya Nakamura Satoru Watano

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

pp.c23-00168, (Released:2023-04-22)

参考文献数

46

被引用文献数

1

---

A rotary tableting machine is used for the continuous tableting process. Tableting conditions often result in capping, leading to serious problems during production. Several studies have been conducted to predict the tablet capping tendency. However, as most previous studies were conducted using a compaction simulator, there is a lack of technology that can be readily applied during actual production. Therefore, the present study aimed to develop a novel method for predicting tablet capping in a rotary tableting machine. We hypothesized that capping occurs when residual stress of the tablet inside a die exceeds the critical stress immediately before ejection. Residual stress was evaluated by measuring the in-line die-wall pressure in a rotary tableting machine. Additionally, critical stress was estimated from the tablet strength inside the die using the Rumpf’s equation. The critical and residual stresses were compared to determine the capping tendency to some extent. The findings of this study will substantially contribute to the rapid detection of tablet capping during tablet production.

著者

Qi Zhang Peizheng Yan Pan Zhao Dongsheng Zhao Heran Cao Jing Lu Beibei Mao

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.2, pp.120-128, 2023-02-01 (Released:2023-02-01)

参考文献数

35

被引用文献数

1

---

Mechanistic target of rapamycin (mTOR) is an effective anti-tumor drug target. Several mTOR kinase inhibitors have entered clinical research, but there are still challenges of potential toxicity. As a new type of targeted drug, proteolysis targeting chimeras (PROTACs) have features of low dosage and low toxicity. However, this approach has been rarely reported to involve mTOR degradation. In this study, the mTOR kinase inhibitor MLN0128 was used as the ligand to the protein of interest and conjugated with pomalidomide by diverse intermediate linkage chains. Several potential small molecule PROTACs for the degradation of mTOR were designed and synthesized. PROTAC compounds exhibited mTOR inhibitory activity and suppressed MCF-7 cell proliferation. The representative compound P1 could inhibit the expression of mTOR downstream proteins and the growth of cancer cells by inducing autophagy but not affecting the cell cycle and not inducing apoptosis.