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Papers - OHE Tomoyuki

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Development of a fluorescent-labeled trapping reagent to evaluate the risk posed by acyl-CoA conjugates

Shibazaki C., Mashino T., Ohe T.

Drug Metabolism and Pharmacokinetics 52 100509 2023.10

Research paper (scientific journal), Joint Work, Last author, Corresponding author, Accepted

Fullerene derivatives as inhibitors of the SARS-CoV-2 main protease

Katagishi D., Yasuda D., Takahashi K., Nakamura S., Mashino T., Ohe T.

Bioorganic and Medicinal Chemistry Letters 80 129121 2023.01

Research paper (scientific journal), Joint Work, Last author, Corresponding author, Accepted

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Development of p62-Keap1 protein–protein interaction inhibitors as doxorubicin-sensitizers against non-small cell lung cancer

Daisuke Yasuda, Ippei Yoshida, Riyo Imamura, Daiki Katagishi, Kyoko Takahashi, Hirotatsu Kojima, Takayoshi Okabe, Yoshinobu Ichimura, Masaaki Komatsu, Tadahiko Mashino, Tomoyuki Ohe

Results in Chemistry 4 100609 2022.10

Research paper (scientific journal), Joint Work, Last author, Accepted

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Formation of Reactive Metabolites of Benzbromarone in Humanized-Liver Mice

Cho N., Suemizu H., Kamimura H., Ohe T., Ito F., Akita H., Kobayashi K.

Drug Metabolism and Pharmacokinetics 47 100467 2022.08

Research paper (scientific journal), Accepted

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Synthesis and evaluation of tofacitinib analogs designed to mitigate metabolic activation

Tateishi Y., Shibazaki C., Takahashi K., Nakamura S., Kazuki Y., Mashino T., Ohe

Drug Metabolism and Pharmacokinetics 43 100439 2022.04

Research paper (scientific journal), Joint Work, Accepted

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A bis-pyridinium fullerene derivative significantly induces apoptosis through the generation of ROS in BCR-ABL-positive leukemia cells

Sumi, K., Tago, K., Nakazawa, Y., Takahashi, K., Ohe, T., Mashino, T., Funakoshi-Tago, M.

Eur J Pharmacol 916 ( 5 ) 174714 2022.02

Research paper (scientific journal), Joint Work, Accepted

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Novel mechanism by a bis-pyridinium fullerene derivative to induce apoptosis by enhancing the MEK-ERK pathway in a ROS-independent manner in BCR-ABL-positive CML-derived K562 cells

Sumi, K., Tago, K., Nakazawa, Y., Takahashi, K., Ohe, T., Mashino, T., Funakoshi-Tago, M.

Int J Mol Sci 23 ( 2 ) 749 2022.01

Research paper (scientific journal), Joint Work, Accepted

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A pyridinium‑type fullerene derivative suppresses primary effusion lymphoma cell viability via the downregulation of the Wnt signaling pathway through the destabilization of β‑catenin

Kadota A., Moriguchi M., Watanabe T., Sekine Y., Nakamura S., Yasuno T., Ohe T., Mashino T., Fujimuro M.

Oncology Reports 47 46 2022.01

Research paper (scientific journal), Joint Work, Accepted

Development of a Fluorescent-Labeled Trapping Reagent to Detect Reactive Acyl Glucuronides

Shibazaki, C., Mashita O.,Takahashi K., Nakamura, S., Mashino T., Ohe T.

Chemical Research in Toxicology 34 ( 11 ) 2343 - 2352 2021.11

Research paper (scientific journal), Joint Work, Accepted

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Novel pyridinium-type fullerene derivatives as multitargeting inhibitors of HIV-1 reverse transcriptase, HIV-1 protease, and HCV NS5B polymerase

Kobayashi T, Yasuno T, Takahashi K, Nakamura S, Mashino T, Ohe T

Bioorganic & Medicinal Chemistry Letters 49 128267 2021.10

Research paper (scientific journal), Joint Work, Accepted

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Mitochondrial reactive oxygen species trigger metformin-dependent antitumor immunity via activation of Nrf2/mTORC1/p62 axis in tumor infiltrating CD8T lymphocytes

Nishida M, Yamashita N, Ogawa T, Koseki K, Warabi E, Ohe T, Komatsu M, Kawakami E, Shiroguchi K, Udono H

J Immunotherapy of Cancer 9 ( 9 ) e002954 2021.10

Research paper (scientific journal), Joint Work, Accepted

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Development of Fluorescent-Labeled Trapping Reagents Based on Cysteine to Detect Soft and Hard Electrophilic Reactive Metabolites

Shibazaki C., Ohe T,. Takahashi K., Nakamura S., Mashino T.

Drug Metabolism and Pharmacokinetics 39 100386 2021.08

Research paper (scientific journal), Joint Work, Accepted

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p62/SQSTM1-droplet serves as a platform for autophagosome formation and anti-oxidative stress response

Kageyama, S., Gudmundsson, S., Sou, Y., Ichimura, Y.,, Tamura, N., Kazuno, S., Ueno, T., Miura, Y.,Noshiro, D., Abe, M., Mizushima, T., Miura, N., Okuda, S., Motohashi, H., Lee, J-A., Sakimura, K., Ohe, T., Noda, N., Waguri, S., Eskelinen, E-L., Komatsu, M.

Nature Communications (Nature Communications) 12 ( 1 ) 16 2021.01

Research paper (scientific journal), Joint Work, Accepted

© 2021, The Author(s). Autophagy contributes to the selective degradation of liquid droplets, including the P-Granule, Ape1-complex and p62/SQSTM1-body, although the molecular mechanisms and physiological relevance of selective degradation remain unclear. In this report, we describe the properties of endogenous p62-bodies, the effect of autophagosome biogenesis on these bodies, and the in vivo significance of their turnover. p62-bodies are low-liquidity gels containing ubiquitin and core autophagy-related proteins. Multiple autophagosomes form on the p62-gels, and the interaction of autophagosome-localizing Atg8-proteins with p62 directs autophagosome formation toward the p62-gel. Keap1 also reversibly translocates to the p62-gels in a p62-binding dependent fashion to activate the transcription factor Nrf2. Mice deficient for Atg8-interaction-dependent selective autophagy show that impaired turnover of p62-gels leads to Nrf2 hyperactivation in vivo. These results indicate that p62-gels are not simple substrates for autophagy but serve as platforms for both autophagosome formation and anti-oxidative stress.

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Fullerene derivatives as dual inhibitors of HIV-1 reverse transcriptase and protease

Yasuno, T., Ohe, T., Kataoka, H., Hashimoto, K., Ishikawa, Y., Furukawa, K., Tateishi, Y., Kobayashi, T., Takahashi, K., Nakamura, S., Mashino, T,

Bioorganic & Medicinal Chemistry Letters (Bioorganic and Medicinal Chemistry Letters) 31 127675 2021.01

Research paper (scientific journal), Joint Work, Accepted, ISSN 0960894X

© 2020 Elsevier Ltd In the present study, we newly synthesized three types of novel fullerene derivatives: pyridinium-type derivatives trans-3a and 4a-5b, piperidinium-type derivative 9, and proline-type derivatives 10a-12. Among the assessed compounds, 5a, 10e, 10f, 10i, 11a-d, and 12 were found to inhibit both HIV reverse transcriptase and HIV protease (HIV-PR), with IC50 values in the low micromolar range being observed. Regarding HIV-PR inhibition activity, proline-type derivatives 11a-11d and 12, bearing an alkyl chain between the hydroxylmethylcarbonyl (HMC) moiety and pyrrolidine ring, were more potent than other derivatives. This result might indicate that connecting HMC moieties with proline-type fullerene derivatives through properly sized alkyl chain leads to improved HIV-PR inhibitory activity.

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Development of Novel Diclofenac Analogs Designed to Avoid Metabolic Activation and Hepatocyte Toxicity

Tateishi, Y., Ohe, T., Ogawa, M., Takahashi, K., Nakamura, S., Mashino, T.

ACS Omega (ACS Omega) 5 ( 50 ) 32608 - 32616 2020.12

Research paper (scientific journal), Joint Work, Accepted

© Diclofenac (DCF) is widely used as a nonsteroidal anti-inflammatory drug; however, it is associated with severe liver injury. This adverse reaction is thought to be related to the reactive quinone imine (QI) and acyl glucuronide (AG) metabolites of DCF, but it remains controversial which reactive metabolites mainly contribute to DCF-induced toxicity. In this study, we synthesized five types of DCF analogs that were designed to mitigate the formation of reactive QI and/or AG metabolites and evaluated their metabolic stability, cyclooxygenase (COX) inhibitory activity, and toxicity to cryopreserved human hepatocytes. Compounds with fluorine at the 5- A nd 4-positions of aromatic rings exhibited modest and high metabolic stability to oxidation by cytochrome P450, respectively, but induced cytotoxicity comparable to DCF. Replacing the carboxylic group of DCF with its bioisosteres was effective in terms of stability to oxidative metabolism and glucuronidation; however, sulfonic acid and sulfonamide groups were not preferable for COX inhibition, and tetrazole-containing analogs induced strong cytotoxicity. On the other hand, compounds that have fluorine at the benzylic position were resistant to glucuronidation and showed little toxicity to hepatocytes. In addition, among these compounds, those with hydrogen at the 4-position (2a and 2c) selectively inhibited the COX-2 enzyme. Throughout these data, it was suggested that compounds 2a and 2c might be novel safer and more efficacious drug candidates instead of DCF.

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Inhibitors of the protein–protein interaction between phosphorylated p62 and Keap1 attenuate chemoresistance in a human hepatocellular carcinoma cell line

Yasuda D., Ohe T., Takahashi K., Imamura R., Kojima H., Okabe T., Ichimura Y., Komatsu M., Yamamoto M., Nagano T., Mashino T.

Free Radical Research 54 ( 11-12 ) 859 - 871 2020.03

Research paper (scientific journal), Accepted, ISSN 10715762

© 2020, © 2020 Informa UK Limited, trading as Taylor & Francis Group. Resistance to anticancer agents has been an obstacle to developing therapeutics and reducing medical costs. Whereas sorafenib is used for the treatment of human hepatocellular carcinoma (HCC), resistance limits its efficacy. p62, a multifunctional protein, is overexpressed in several HCC cell lines, such as Huh-1 cells. Phosphorylated p62 (p-p62) inhibits the protein–protein interaction (PPI) between Keap1 and Nrf2, resulting in the Nrf2 overactivation that causes drug resistance. We have found a unique Nrf2 inactivator, named K67, that inhibited the PPI between Keap1 and p-p62 and attenuated sorafenib resistance in Huh-1 cells. Herein, we designed and synthesised novel K67 derivatives by modification of the substituent at the 4-position of the two benzenesulfonyl groups of K67. Although these new derivatives inhibited the Keap1-p-p62 PPI to a level comparable to or weaker than that of K67, the isopropoxy derivative enhanced the sensitivity of Huh-1 cells to sorafenib to a greater extent than K67 without any influence on the viability of Huh-7 cells, which is a non-resistant HCC cell line. The isopropoxy derivative also increased the sensitivity of Huh-1 cells to regorafenib, which suggests that this derivative has the potential to be used as an agent to overcome chemoresistance based on Nrf2 inactivation.

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Synthesis and Evaluation of Nevirapine Analogs to Study the Metabolic Activation of Nevirapine

Yasuhiro Tateishi, Tomoyuki Ohe, Daisuke Yasuda, Kyoko Takahashi, Shigeo Nakamura, Yasuhiro Kazuki, Tadahiko Mashino

Drug Metabolism and Pharmacokinetics (Drug Metabolism and Pharmacokinetics) 35 ( 2 ) 238 - 243 2020.02

Research paper (scientific journal), Joint Work, Accepted, ISSN 13474367

Nevirapine (NVP) is widely used as a non-nucleoside reverse transcriptase inhibitor of HIV-1, however, it is associated with severe skin and liver injury. The mechanisms of these adverse reactions are not yet clear, but the metabolic activation of NVP is thought to be related to the injury process. Until now, several metabolic activation pathways of NVP have been reported. In this study, in order to identify the reactive metabolite of NVP mainly responsible for CYP inhibition and liver injury, we synthesized five NVP analogs designed to avoid the proposed bioactivation pathway and evaluated their metabolic stabilities, CYP3A4 time-dependent inhibitory activities, and cytotoxicity. As a result, only a pyrimidine analog of NVP, which could avoid the formation of a reactive epoxide intermediate, did not inhibit CYP3A4. Outside of this compound, the other synthesized compounds, which could avoid the generation of a reactive quinone-methide intermediate, inhibited CYP3A4 equal to or stronger than NVP. The pyrimidine analog of NVP did not induce cytotoxicity in HepG2 and transchromosomic HepG2 cells, expressing major four CYP enzymes and CYP oxidoreductase. These results indicated that the epoxide intermediate of NVP might play an important role in NVP-induced liver injury.

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Synthesis and antitumor activity of novel pyridinium fullerene derivatives

Takumi Yasuno, Tomoyuki Ohe, Hitomi Ikeda, Kyoko Takahashi, Shigeo Nakamura, Tadahiko Mashino

International Journal of Nanomedicine 14 6325 - 6337 2019.08

Research paper (scientific journal), Joint Work, Accepted, ISSN 11769114

Purpose: We have previously reported that some cationic fullerene derivatives exhibited anticancer activity, and they are expected to be a potential lead compound for an anti-drug resistant cancer agent. However, they are bis-adducts and a mixture of multiple regioisomers, which cannot be readily separated due to the variability of substituent positions on the fullerene cage. To overcome this issue, we evaluated the antiproliferative activities of a set of mono-adduct derivatives and examined their structure-activity relationship. In addition, the in vivo antitumor activity of selected derivatives was also examined. Methods: Nineteen pyridinium fullerene derivatives were newly designed and synthesized in this study. Their antiproliferative activities were evaluated using several cancer cell lines including drug-resistant cells. Furthermore, in vivo antitumor activity of several derivatives was investigated in mouse xenograft model of human lung cancer. Results: The derivatives inhibited the proliferation of cancer cell lines, including cisplatin-resistant cells and doxorubicin-resistant cells. It was also shown that compound 10 (10 μM), 13 (10 μM) and cis-14 (10 μM) induced the intracellular oxidative stress. In addition, compound 13 (20 mg/kg) and cis-14 (15 mg/kg) significantly exhibited antitumor activity in mouse xenograft model of human lung cancer. Conclusion: We synthesized a novel set of mono-adduct fullerene derivatives functionalized with pyridinium groups and found that most of them show potent antiproliferative activities against cancer cell lines and some of them show significant antitumor activities in vivo. We propose that these fullerene derivatives serve as the lead compounds for a novel type of antitumor agents.

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N-Acetyl cysteine prevents activities of STAT3 inhibitors, Stattic and BP-1-102 independently of its antioxidant properties

Yuki Uchihara, Tomoyuki Ohe, Tadahiko Mashino, Takayuki Kidokoro, Hiroomi Tamura and Megumi Funakoshi-Tago

Pharmacological Reports 71 ( 6 ) 1067 - 1078 2019.05

Research paper (scientific journal), Joint Work, Accepted, ISSN 17341140

Inhibitors for signal transducer and activator of transcription 3 (STAT3), Stattic, BP-1-102, and LLL12 significantly induce apoptosis in transformed Ba/F3 cells expressing an oncogenic fusion protein, nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) that induces the activation of STAT3. We found that the antioxidant reagent, N-acetyl cysteine (NAC) prevented the abilities of Stattic and BP-1-102, but not LLL12 to induce apoptosis in transformed cells expressing NPM-ALK, providing a novel problem in use of STAT3 inhibitors. We herein investigated the mechanisms how NAC prevented the effects of Sttatic and BP-1-102. Methods: Ba/F3 cells expressing NPM-ALK and SUDHL-1 cells were treated with antioxidants such as NAC, Trolox or edaravone in combination with STAT3 inhibitors. Phosphorylation of STAT3, cell proliferation rate, cell viability, cell cycle, internucleosomal DNA fragmentation and the intracellular accumulation of reactive oxygen species (ROS) was investigated. The binding of STAT3 inhibitors and NAC was analyzed by LC–MS. Results: NAC but not Trolox and edaravone diminished the abilities of Stattic and BP-1-102 to induce apoptosis in cells expressing NPM-ALK. The ROS levels in cells expressing NPM-ALK were not markedly affected by the treatments with Stattic and BP-1-102 in combination with NAC, suggesting that NAC inhibited the activity of Stattic and BP-1-102 independent of its antioxidant activity. LC–MS analysis revealed that NAC directly bound to Stattic and BP-1-102. Furthermore, these NAC adducts exhibited no cytotoxicity, and failed to affect the activity of STAT3. Conclusions: NAC antagonizes the activities of Stattic and BP-1-102, which inhibit STAT3 activation by interacting with cysteine residues in STAT3.

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Synthesis of novel benzbromarone derivatives designed to avoid metabolic activation

Ohe T, Umezawa R, Kitagawara Y, Yasuda D, Takahashi K, Nakamura S, Abe A, Sekine S, Ito K, Okunushi K, Morio H, Furihata T, Anzai N, Mashino T.

Bioorganic and Medicinal Chemistry Letters 28 ( 23-24 ) 3708 - 3711 2018.10

Research paper (scientific journal), Joint Work, Accepted, ISSN 0960894X

We synthesized six novel BBR derivatives that were designed to avoid metabolic activation via ipso-substitution and evaluated for their degree of toxicity and hURAT1 inhibition. It was found that all of the derivatives demonstrate lower cytotoxicity in mouse hepatocytes and lower levels of metabolic activation than BBR, while maintaining their inhibitory activity toward the uric acid transporter. We propose that these derivatives could serve as effective uricosuric agents that have much better safety profiles than BBR.

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Hit-to-Lead in Academia: Discovery of a Protein-Protein Interaction Inhibitor of Keap1-Nrf2

Daisuke Yasuda, Rika Obata, Kyoko Takahashi, Tomoyuki Ohe, Tadahiko Mashino

YAKUGAKU ZASSHI 138 ( 8 ) 1059 - 1065 2018.08

Research paper (scientific journal), Joint Work, Accepted

Discovery of benzo[g]indoles as a novel class of non-covalent Keap1-Nrf2 protein-protein interaction inhibitor

Yasuda, D., Yuasa, A., Obata, R., Nakajima M., Takahashi, K., Ohe, T., Ichimura, Y., Komatsu, M., Yamamoto, M., Imamura, R., Kojima, H., Okabe, T., Nagano, T., and Mashino, T.

Bioorg Med Chem Lett 27 ( 22 ) 5006 - 5009 2017.11

Research paper (scientific journal), Joint Work, Accepted

alpha-Tocopherol attenuates the anti-tumor activity of crizotinib against cells transformed by NPM-ALK

Uchihara Y, Ueda F, Tago K, Nakazawa Y, Ohe T, Mashino T, Yokota S, Kasahara T, Tamura H, and Funakoshi-Tago M

PLOS ONE 12 ( 8 ) e0183003 2017.08

Research paper (scientific journal), Joint Work, Accepted

ヒトや野生生物における医薬品、環境化学物質の安全性評価の精度向上にむけて -代謝的活性化、種差、エピジェネティクスの観点から肝毒性を示す医薬品の代謝活性化機構の解析とそれに基づいた創薬戦略

Ohe T., Takahashi K., Nakamura S., Mashino T.

YAKUGAKU ZASSHI 137 ( 3 ) 249 - 255 2017.03

Research paper (scientific journal), Joint Work, Accepted

Synthesis of Keap1-phosphorylated p62 and Keap1-Nrf2 protein-protein interaction inhibitors and their inhibitory activity

Yasuda, D., Nakajima, M., Yuasa, A., Obata, R., Takahashi, K., Ohe, T., Ichimura, Y., Komatsu, M., Yamamoto, M., Imamura, R., Kojima, H., Okabe, T., Nagano, T., and Mashino, T.

Bioorg Med Chem Lett 26 ( 24 ) 5956 - 5959 2016.12

Research paper (scientific journal), Joint Work, Accepted

Preparation and antioxidant/pro-oxidant activities of 3-monosubstituted 5-hydroxyoxindole derivatives

Yasuda, D., Takahashi, K., Ohe, T., Nakamura, S., and Mashino, T.

J Clin Biochem Nutr 59 ( 3 ) 165 - 173 2016.11

Research paper (scientific journal), Joint Work, Accepted

Potential suppressive effects of two C60-fullerene derivatives on acquired immunity

Toshiro Hirai, Yasuo Yoshioka, Asako Udaka, Eiichiro Uemura, Tomoyuki Ohe, Hisae Aoshima, Jian-Qing Gao, Ken Kokubo, Takumi Oshima, Kazuya Nagano, Kazuma Higashisaka, Tadahiko Mashino, Yasuo Tsutsumi

Nanoscale Research Letters 11 449 2016.10

Research paper (scientific journal), Joint Work, Accepted

Novel fullerene derivatives as dual inhibitors of Hepatitis C virus NS5B polymerase and NS3/4A protease

Hiroki Kataoka, Tomoyuki Ohe, Kyoko Takahashi, Shigeo Nakamura, Tadahiko Mashino

Bioorg Med Chem Lett 26 4565 - 4567 2016.10

Research paper (scientific journal), Joint Work, Accepted

p62/Sqstm1 promotes malignancy of HCV-positive hepatocellular carcinoma through Nrf2-dependent metabolic reprogramming

Saito T, Ichimura Y, Taguchi K, Suzuki T, Mizushima T, Takagi K, Hirose Y, Nagahashi M, Iso T, Fukutomi T, Ohishi M, Endo K, Uemura T, Nishito Y, Okuda S, Obata M, Kouno T, Imamura R, Tada Y, Obata R, Yasuda D, Takahashi K, Fujimura T, Pi J, Lee MS, Ueno T, Ohe T, Mashino T, Wakai T, Kojima H, Okabe T, Nagano T, Motohashi H, Waguri S, Soga T, Yamamoto M, Tanaka K, Komatsu M

Nature Communications 7 ( 12030 ) 1 - 16 2016.06

Research paper (scientific journal), Joint Work, Accepted

A proline-type fullerene derivative inhibits adipogenesis by preventing PPARgamma activation

Megumi Funakoshi-Tagoa, Takahiro Hattori, Fumihito Ueda, Kenji Tago, Tomoyuki Ohe, Tadahiko Mashino, Hiroomi Tamura

Biochemistry and Biophysics Reports 20 ( 1 ) 258 - 263 2016.01

Research paper (scientific journal), Joint Work, Accepted

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Novel Bioactivation Pathway of Benzbromarone Mediated by Cytochrome P450

Yumina Kitagawara, Tomoyuki Ohe, Kumiko Tachibana, Kyoko Takahashi, Shigeo Nakamura, and Tadahiko Mashino

Drug Metab Dispos 43 1303 - 1306 2015.09

Research paper (scientific journal), Joint Work, Accepted

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The human immunodeficiency virus-reverse transcriptase inhibition activity of novel pyridine/pyridinium-type fullerene derivatives

Takumi Yasuno, Tomoyuki Ohe, Kyoko Takahashi, Shigeo Nakamura, Tadahiko Mashino

Bioorg Med Chem Lett 25 ( 16 ) 3226 - 3229 2015.08

Research paper (scientific journal), Joint Work, Accepted

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Blood-Brain Barrier Pharmacoproteomics-based Reconstruction of the In-Vivo Brain Distribution of P-glycoprotein Substrates in Cynomolgus Monkeys.

Uchida Y, Wakayama K, Ohtsuki S, Chiba M, Ohe T, Ishii Y, Terasaki T.

J Pharmacol Exp Ther 350 578-588 2014.09

Research paper (scientific journal), Joint Work, Accepted

Pyrrolidinium fullerene induces apoptosis by activation of procaspase-9 via suppression of Akt in primary effusion lymphoma.

Watanabe T, Nakamura S, Ono T, Ui S, Yagi S, Kagawa H, Watanabe H, Ohe T, Mashino T, Fujimuro M.

Biochem Biophys Res Commun 451 93-100 2014.08

Research paper (scientific journal), Joint Work, Accepted

Effect of chemical modification on the ability of pyrrolidinium fullerene to induce apoptosis of cells transformed by JAK2 V617F mutant.

Funakoshi-Tago M, Tsukada M, Watanabe T, Mameda Y, Tago K, Ohe T, Nakamura S, Mashino T, Kasahara T.

Int Immunopharmacol 20 258-263 2014.03

Research paper (scientific journal), Joint Work, Accepted

Antioxidant activities of 5-hydroxyoxindole and its 3-hydroxy-3-phenacyl derivatives: The suppression of lipid peroxidation and intracellular oxidative stress.

Yasuda D, Takahashi K, Ohe T, Nakamura S, Mashino T.

Bioorg Med Chem 21 7709-7714 2013.12

Research paper (scientific journal), Joint Work, Accepted

Synthesis, radical scavenging activity and structurer-activity relationship of uric acid analogs.

Yasuda D, Takahashi K, Kakinoki T, Tanaka Y, Ohe T, Nakamura S, Mashino T.

MedChemComm 4 527-529 2013.01

Research paper (scientific journal), Joint Work, Accepted

A novel method for the determination of the site of glucuronidation by ion mobility spectrometry-mass spectrometry.

Shimizu A, Ohe T, Chiba M.

Drug Metab Dispos 40 1456-1459 2012.05

Research paper (scientific journal), Joint Work, Accepted

Pharmacokinetic and pharmacodynamic properties of the glucokinase activator MK-0941 in rodent models of type 2 diabetes and healthy dogs.

Eiki J, Nagata Y, Futamura M, Sasaki-Yamamoto K, Iino T, Nishimura T, Chiba M, Ohyama S, Yoshida-Yoshimioto R, Fujii K, Hosaka H, Goto-Shimazaki H, Kadotani A, Ohe T, Lin S, Langdon RB, Berger JP.

Mol Pharmacol 80 1156-1165 2011.12

Research paper (scientific journal), Joint Work, Accepted

Discovery and characterization of a novel potent, selective and orally active inhibitor for mammalian ELOVL6.

Shimamura K, Nagumo A, Miyamoto Y, Kitazawa H, Kanesaka M, Yoshimoto R, Aragane K, Morita N, Ohe T, Takahashi T, Nagase T, Sato N, Tokita S.

Eur J Pharmacol 25 34-41 2010.03

Research paper (scientific journal), Joint Work, Accepted

A trapping method for semi-quantitative assessment of reactive metabolite formation using [35S]cysteine and [14C]cyanide.

Inoue K, Shibata Y, Takahashi H, Ohe T, Chiba M, Ishii Y.

Drug Metab Pharmacokinet 24 245-254 2009.10

Research paper (scientific journal), Joint Work, Accepted

Aromatic substitution reaction of 2-chloropyridines catalyzed by microsomal glutathione S-transferase 1.

Inoue K, Ohe T, Mori K, Sagara T, Ishii Y, Chiba M.

Drug Metab Dispos 37 1797-1800 2009.09

Research paper (scientific journal), Joint Work, Accepted

Discovery of trans-N-[1-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide, a potent and orally active neuropeptide Y Y5 receptor antagonist.

Haga Y, Sakamoto T, Shibata T, Nonoshita K, Ishikawa M, Suga T, Takahashi H, Takahashi T, Takahashi H, Ando M, Murai T, Gomori A, Oda Z, Kitazawa H, Mitobe Y, Kanesaka M, Ohe T, Iwaasa H, Ishii Y, Ishihara A, Kanatani A, Fukami T.

Bioorg Med Chem 17 6971-6982 2009.09

Research paper (scientific journal), Joint Work, Accepted

Identification of positron emission tomography ligands for NPY Y5 receptors in the brain.

Takahashi H, Haga Y, Shibata T, Nonoshita K, Sakamoto T, Moriya M, Ohe T, Chiba M, Mitobe Y, Kitazawa H, Iwaasa H, Ishihara A, Ishii Y, Kanatani A, Fukami T.

Bioorg Med Chem Lett 19 5436-5439 2009.09

Research paper (scientific journal), Joint Work, Accepted

Discovery of pyridone-containing imidazolines as potent and selective inhibitors of neuropeptide Y Y5 receptor.

Ando M, Sato N, Nagase T, Nagai K, Ishikawa S, Takahashi H, Ohtake N, Ito J, Hirayama M, Mitobe Y, Iwaasa H, Gomori A, Matsushita H, Tadano K, Fujino N, Tanaka S, Ohe T, Ishihara A, Kanatani A, Fukami T.

Bioorg Med Chem 17 6106-6122 2009.08

Research paper (scientific journal), Joint Work, Accepted

Aryl urea derivatives of spiropiperidines as NPY Y5 receptor antagonists.

Takahashi T, Haga Y, Sakamoto T, Moriya M, Okamoto O, Nonoshita K, Shibata T, Suga T, Takahashi H, Hirohashi T, Sakuraba A, Gomori A, Iwaasa H, Ohe T, Ishihara A, Ishii Y, Kanatani A, Fukami T.

Bioorg Med Chem Lett 19 3511-3516 2009.07

Research paper (scientific journal), Joint Work, Accepted

5,5-Dimethyl-3-(5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-1-phenyl-3-(trifluoromethyl)-3,5,6,7-tetrahydro-1H-indole-2,4-dione, a potent inhibitor for mammalian elongase of long-chain fatty acids family 6:

Shimamura K, Kitazawa H, Miyamoto Y, Kanesaka M, Nagumo A, Yoshimoto R, Aragane K, Morita N, Ohe T, Takahashi T, Nagase T, Sato N, Tokita S.

J Pharmacol Exp Ther 330 249-256 2009.07

Research paper (scientific journal), Joint Work, Accepted

Discovery of tetrasubstituted imidazolines as potent and selective neuropeptide Y Y5 receptor antagonists: reduced human ether-a-go-go related gene potassium channel binding affinity and potent antiobesity effect.

Sato N, Ando M, Ishikawa S, Jitsuoka M, Nagai K, Takahashi H, Sakuraba A, Tsuge H, Kitazawa H, Iwaasa H, Mashiko S, Gomori A, Moriya R, Fujino N, Ohe T, Ishihara A, Kanatani A, Fukami T.

J Med Chem 52 3385-3392 2009.05

Research paper (scientific journal), Joint Work, Accepted

Design, syntheses, and structure-activity relationships of novel NPY Y5 receptor antagonists: 2-{3-Oxospiro[isobenzofuran-1(3H),4'-piperidin]-1'-yl}benzimidazole derivatives.

Ogino Y, Ohtake N, Nagae Y, Matsuda K, Moriya M, Suga T, Ishikawa M, Kanesaka M, Mitobe Y, Ito J, Kanno T, Ishihara A, Iwaasa H, Ohe T, Kanatani A, Fukami T.

Bioorg Med Chem Lett 18 5010-5014 2008.09

Research paper (scientific journal), Joint Work, Accepted

Syntheses and structure-activity relationships of novel, potent, and selective trans-2-[3-oxospiro[isobenzofuran-1(3H),1'-cyclohexan]-4'-yl]benzimidazole NPY Y5 receptor antagonists.

Ogino Y, Ohtake N, Nagae Y, Matsuda K, Ishikawa M, Moriya M, Kanesaka M, Mitobe Y, Ito J, Kanno T, Ishihara A, Iwaasa H, Ohe T, Kanatani A, Fukami T.

Bioorg Med Chem Lett 18 4997-5001 2008.09

Research paper (scientific journal), Joint Work, Accepted

(9S)-9-(2-hydroxy-4,4-dimethyl-6-oxo-1-cyclohexen-1-yl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthen-1-one, a selective and orally active neuropeptide Y Y5 receptor antagonist.

Sato N, Jitsuoka M, Shibata T, Hirohashi T, Nonoshita K, Moriya M, Haga Y, Sakuraba A, Ando M, Ohe T, Iwaasa H, Gomori A, Ishihara A, Kanatani A, Fukami T.

J Med Chem 51 4765-4770 2008.08

Research paper (scientific journal), Joint Work, Accepted

A neuropeptide Y Y5 antagonist selectively ameliorates body weight gain and associated parameters in diet-induced obese mice.

Ishihara A, Kanatani A, Mashiko S, Tanaka T, Hidaka M, Gomori A, Iwaasa H, Murai N, Egashira S, Murai T, Mitobe Y, Matsushita H, Okamoto O, Sato N, Jitsuoka M, Fukuroda T, Ohe T, Guan X, MacNeil DJ, Van der Ploeg LH, Nishikibe M, Ishii Y, Ihara M, Fukami T.

Proc Natl Acad Sci U S A 103 7154-7158 2006.05

Research paper (scientific journal), Joint Work, Accepted

Effect of P-glycoprotein-mediated efflux on cerebrospinal fluid/plasma concentration ratio.

Ohe T, Sato M, Tanaka S, Fujino N, Hata M, Shibata Y, Kanatani A, Fukami T, Yamazaki M, Chiba M, Ishii Y.

Drug Metab Dispos 31 1251-1254 2003.10

Research paper (scientific journal), Joint Work, Accepted

Evaluation of drug interactions with P-glycoprotein in drug discovery: in vitro assessment of the potential for drug-drug interactions with P-glycoprotein.

Hochman JH, Yamazaki M, Ohe T, Lin JH.

Curr Drug Metab (Bentham Science Publishers ) 3 257 - 273 2002.06

Research paper (scientific journal), Joint Work

In Vitro Identification Studies for P-Glycoprotein-Mediated Transport: Species Difference and Predictability of In Vivo Results.

M. Yamazaki, W. E. Neway, T. Ohe, I.-W. Chen, J. F. Rowe, J. H. Hochman, M. Chiba and J. H. Li

J. Pharmacol. Exp. Ther. 296 723 - 735 2001

Research paper (scientific journal), Joint Work, Accepted

A Typical Y1 Receptor Regulates Feeding Behaviors: Effects of a Potent and Selective Y1 Antagonist, J-115814

A. Kanatani, M. Hata, S. Mashiko, A. Ishihara, O. Okamoto, Y. Haga, T. Ohe, T. Kanno, N. Murai, Y. Ishii, T. Fukuroda, T. Fukami and M. Ihara

Mol. Pharmacol. 59 501 - 505 2001

Research paper (scientific journal), Joint Work, Accepted

Novel metabolic pathway of estrone and 17b-estradiol catalyzed by cytochrome P450.

Ohe T, Hirobe M, Mashino T.

Drug Metab Dispos 28 110-112 2000.01

Research paper (scientific journal), Joint Work, Accepted

Substituent Elimination from para-Substituted Phenols by Cytochrome P450: ipso-Substitution by the Oxygen Atom of the Active Species

T. Ohe, T. Mashino and M. Hirobe

Drug Metab Dispos 25 116 - 122 1997

Research paper (scientific journal), Joint Work, Accepted

Novel Oxidative Pathway of para-Substituted Phenols in Cytochrome P450 Chemical Model: Substituent Elimination Accompanying ipso-Substitution by the Oxygen Atom of the Active Species

T. Ohe, T. Mashino and M. Hirob

Tetrahedron Letters 42 7681 - 7684 1995

Research paper (scientific journal), Joint Work, Accepted

Novel Metabolic Pathway of Arylethers by Cytochrome P450: Cleavage of the Oxygen-Aromatic Ring Bond Accompanying ipso-Substitution by the Oxygen Atom of the Active Species in Cytochrome P450 Models and Cytochrome P450

T. Ohe, T. Mashino and M. Hirobe

Archives of Biochemistry and Biophysics 310 402 - 409 1994

Research paper (scientific journal), Joint Work, Accepted

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