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Laboratory of Medicinal Chemistry

Laboratory of Medicinal Chemistry

Japanese

Welcome to the Laboratory of Medicinal Chemistry !!

We design and synthesize new compounds to evaluate them to find novel drug candidates. Such research field is dealt with midicinal chemistry. Although medicinal chemistry is based on organic chemistry, it is a comprehensive and interdiscrlinary science, which rests on many scientific field like medical science, pharmacology, molecular biology, pharmacokinetics, pharmaceutical science, and so on. We also develop novel photochemical reactions.

Research Achievements

  • Original Articles
  • Lecture/Conference
  • Books/Publications

    • Research Papers : 2023

    Moriya, Y.; Kasahara, Y.; Shimada, M.; Sakakibara, Y.; Fujii, H.; Nagase, H.; Ide, S.; Ikeda, K.; Hall, F. S.; Uhl, G. R.; Sora, I.
    Journal of Pharmacological Sciences,  2023, 151, 135-141.

    The first structure-activity relationship study of oxytocin as a positive allosteric modulator for the µ opioid receptor 
    Mizuguchi, T.; Miyano, K.; Yamauchi, R.; Yoshida, Y.; Takahashi, H.; Yamazaki, A.; Ono, H.; Inagaki, M.; Nonaka, M.; Uezono, Y.; Fujii, H.
    Peptides, 2023, 159, 170901.

    Research Papers : 2022

    Itoh, K.; Ito, S.; Nagao, S.; Tokunaga, K.; Mizuguchi, T.; Karaki, F.; Hirayama, S.; Shibagaki, Y.; Hashimoto. M.; Fujii, H.
    HETEROCYCLES, 2022, 104, 2169-2178.

    The Japanese Herbal Medicine Hangeshashinto Induces Oral Keratinocyte Migration by Mediating the Expression of CXCL12 Through the Activation of Extracellular Signal-Regulated Kinase. 
    Miyano, K.; Hasegawa, S.; Asai, N.; Uzu, M.; Yatsuoka, W.; Ueno, T.; Nonaka, M.;  Fujii, H.; Uezono, Y.
    Frontiers in pharmacology, 2022, 12, 695039.

    Research Papers : 2021

    Uenohara, Y.; Tsumura, S.; Hirayama, S.; Higashi, E.; Watanabe, Y.; Gouda, H.; Nagase, H.; Fujii, H.
    Bioorganic & Medicinal Chemistry, 2021, 53, 116552.
     
    Karasawa, Y.; Miyano, K.; Fujii, H.; Mizuguchi, T.; Kuroda, Y.; Nonaka, M.; Komatsu, A.; Ohshima, K.; Yamaguchi, M.; Yamaguchi, K.; Iseki, M.; Uezono, Y.; Hayashida, M.
    Molecules. 2021, 26. 6079.

    Oxytocin Is a Positive Allosteric Modulator of κ-Opioid Receptors but Not δ-Opioid Receptors in the G Protein Signaling Pathway.
    Miyano, K.; Yoshida, Y.; Hirayama, S.; Takahashi, H.; Ono, H.; Meguro, Y.; Manabe, S.; Komatsu, A.; Nonaka, M.; Mizuguchi, T.; Fujii, H.; Higami, Y.; Narita, M.; Uezono, Y.
    Cells, 2021, 10 2651.

    Catalyst-free photooxidation reaction from 1,4-dihydropyridazine to pyridazine under air.
    Karak, F.; Kiguchi, T.; Itoh, K.; Sato, N.; Konishi, K; Fujii, H.
    Tetrahedron, 2021, 97, 132411.
     

    Identification of a Putative β-Arrestin Superagonist of the Growth Hormone Secretagogue Receptor (GHSR). 
    Karaki, F.; Oki, T.; Sakao, Y.; Sato, N.; Hirayama, S.; Miyano, K.; Uezono, Y.; Fujii, H.
    ChemMedChem. 2021. 16. 3463-3476.


    Visible-Light-Induced Synthesis of 1,2,3,4-Tetrahydroquinolines through Formal [4+2] Cycloaddition of Acyclic α,β-Unsaturated Amides and Imides with N,N-Dialkylanilines.
    Itoh, K.; Nagao, S.; Tokunaga, K.; Hirayama, S.; Karaki, F.; Mizuguchi, T.; Nagai, K.; Sato, N.; Suzuki, M.; Hashimoto, M.; Fujii, H.
    Chem. Eur. J., 2021, 27, 5171-5179.

    Research Papers : 2020

    Effects of N-Substituents on the Functional Activities of Naltrindole Derivatives for the δ Opioid Receptor: Synthesis and Evaluation of Sulfonamide Derivatives.
    Iwamatsu, C.; Hayakawa, D.; Kono, T.; Honjo, A.; Ishizaki, S.; Hirayama, S.; Gouda, H.; Fujii, H.
    Molecules, 2020, 15, 3792.

    Enhancement of the rewarding effects of 3,4-methylenedioxymethamphetamine in orexin knockout mice.
    Mori, T.; Uzawa, N.; Masukawa, D.; Hirayama, S.; Iwase, Y.; Hokazono, M.; Udagawa, Y.; Suzuki, T.
    Behav. Brain Res., 2020, 396, 112802.

    Discovery of δ opioid receptor full agonists lacking a basic nitrogen atom and their antidepressant-like effects.
    Fujii, H.; Uchida, Y.; Shibasaki, M.; Nishida, M.; Yoshioka, T.; Kobayashi, R.; Honjo, A.; Itoh, K.; Yamada, D.; Hirayama, S.; Saitoh, A.
    Bioorg. Med. Chem. Lett., 2020, 30, 127176.

    Japanese Herbal Medicine Ninjinyoeito Mediates Its Orexigenic Properties Partially by Activating Orexin 1 Receptors.
    Miyano, K.; Ohshima, K.; Suzuki, N.; Furuya, S.; Yoshida, Y.; Nonaka, M.; Higami, Y.; Yoshizawa, K.; Fujii, H.; Uezono, Y.
    Front. Nutr., 2020, 7, 5.

    Synthesis of 1,2,5-Oxadiazinane Derivatives by Photochemical Cycloaddition of Nitrones with Diaminomethanes.
    Itoh, K.; Takashino, A.; Ohtsuka, A.; Kobe, M.; Sawamura, S.; Kato, R.; Hirayama, S.; Karaki, F.; Mizuguchi, T.; Sato, N.; Tokunaga, K.; Toda, Y.; Suga, H.; Ishida, H.; Fujii, H.
    ChemPhotoChem, 2020, 4, 388-392.

    Research Papers : 2019

    A Novel Lead Identification Strategy: Screening an sp3-rich and Lead-like Compound Library Composed of 7-Azanorbornane Derivatives.
    Karaki, F.; Umemoto, S.; Ashizawa, K.; Sato, N.; Oki, T.; Ogino, T.; Ishibashi, N.; Someya, R.; Miyano, K.; Hirayama, S.; Uezono, Y.; Fujii, H.
    ChemMedChem, 2019, 14, 1840-1848.

    Ligand-Dependent Site-Selective Suzuki Cross-Coupling of 4-Bromopyrazol-5-yl Triflates.
    Sakakibara, R.; Itoh, K.; Fujii, H.
    J. Org. Chem., 2019, 84, 11474-11481.

    Development of Novel δ Opioid Receptor Inverse Agonists without a Basic Nitrogen Atom and Their Antitussive Effects in Mice.
    Higashi, E.; Hirayama, S.; Nikaido, J.; Shibasaki, M.; Kono, T.; Honjo, A.; Ikeda, H.; Kamei, J.; Fujii, H.
    ACS Chem. Neurosci., 2019, 10, 3939-3945.

    THE PRACTICE OF THE SELECTIVE SYNTHETIC METHOD OF ASYMMETRICAL 1,3,5-TRIOXAZATRIQUINANE DERIVATIVES COMPRISED OF THREE DISTINCT CARBONYL COMPOUNDS.
    Hirayama, S.; Obayashi, K.; Wada, N.; Ohyama, K.; Fuku, S.; Koyano, K.; Karaki, F.; Itoh, K.; Nagase, H.; Fujii H.
    Heterocycles, 2019, 99, 1003-1019.

    Discovery of δ Opioid Receptor Full Inverse Agonists and Their Effects on Restraint Stress-induced Cognitive Impairment in Mice.
    Hirayama, S.; Iwai, T.; Higashi, E.; Nakamura, M.; Iwamatsu, C.; Itoh, K.; Nemoto, T.; Tanabe, M.; Fujii, H.
    ACS Chem. Neurosci., 2019, 10, 2237-2242.

    Novel asymmetric photodimerization reaction of coumarin derivatives bearing a chiral 2-oxazolidinone auxiliary.
    Itoh, K.; Odate, F.; Karikomi, T.; Obe, K.; Miyamori, T.; Kamiya, H.; Yoza, K.; Nagai, K.; Fujii, H.; Suga, H.; Tokunaga, K.
    RCS Adv., 2019, 9, 12365-12369.

    A facile preparation of functional cycloalkynes via an azide-to-cycloalkyne switching approach.
    Yoshida, S.; Kuribara, T.; Ito, H.; Meguro, T.; Nishiyama, Y.; Karaki, F.; Hatakeyama, Y.; Koike, Y.; Kii, I.; Hosoya, T.
    Chem. Commun., 2019, 55, 3556-3559.

    Research Papers : 2018

    Enantioselective synthesis of 8-azabicyclo[3.2.1]octanes via asymmetric 1,3-dipolar cycloadditions of cyclic azomethine ylides using a dual catalytic system.
    Suga, H.; Yoshiwara, H.; Yamaguchi, T.; Bando, T.; Taguchi, M.; Inaba, A.; Goto, Y.; Kikuchi, A.; Itoh, K.; Toda, Y.
    Chem. Commun., 2018, 55, 1552-1555.

    A deprotection procedure using SO3H silica gel to remove non-silyl protecting groups.
    Karaki, F.; Kuwada, M.; Tajiri, S.; Kanda, M.; Yanai, M.; Kamimura, M.; Itoh, K.; Fujii, H.
    Synth. Commun., 2018, 49, 212-220.

    Acetic Anhydride-Mediated Retro-Ene Reaction via a [4.4.3]Propellane Skeleton Intermediate Containing a Quaternary Ammonium Linkage.
    Kutsumura, N.; Okada, T.; Imaide, S.; Fujii, H.; Nagase, H.
    Synthesis, 2018, 50, 4263-4269.

    LEWIS ACID CATALYSIS IN INTERMOLECULAR [2+2] PHOTOCYCLOADDITION OF COUMARIN-3-CARBOXAMIDE BEARING 2-OXAZOLIDINONE AUXILIARY WITH n-PROPYL VINYL ETHER AND VINYL PIVALATE.
    Itoh, K.; Matsuura, J.; Kamiya, H.; Kudo, R.; Takahashi, Y.; Hashimoto, Y.; Yoza, K.; Tokunaga, K.; Fujii, H.; Suga H.
    Heterocycles, 2018, 97, 591-603.

    Neuropeptide oxytocin enhances μ opioid receptor signaling as a positive allosteric modulator.
    Meguro, Y.; Miyano, K.; Hirayama, S.; Yoshida, Y.; Ishibashi, N.; Ogino, T.; Fujii, Y.; Manabe, S.; Eto, M.; Nonaka, M.; Fujii, H.; Ueta, Y.; Narita, M.; Sata, N.; Yada, T.; Uezono, Y.
    J. Pharmacol. Sci., 2018, 137, 67-75.

    Three-Component Reactions of Diazoesters, Aldehydes, and Imines Using a Dual Catalytic System Consisting of a Rhodium(II) Complex and a Lewis Acid.
    Toda, Y.; Kaku, W.; Tsuruoka, M.; Shinogaki, S.; Abe, T.; Kamiya, H.; Kikuchi, A.; Itoh, K.; Suga, H.
    Org. Lett., 2018, 20, 2659-2662.

    SYNTHESIS OF NOVEL 1,3-DIOXA-5-THIAZATRIQUINANE AND 1-OXA-3,5-DITHIAZATRIQUINANE DERIVATIVES AND THEIR PHARMACOLOGIES.
    Ohshita, R.; Kutsumura, N.; Nagumo, Y.; Yamamoto, N.; Saitoh, T.; Hirayama, S.; Fujii, H.; Nagase, H.
    Heterocycles, 2018, 97, 687-695.

    Exploration of DPP-IV inhibitors with a novel scaffold by multistep in silico screening.
    Uchida, T.; Wakasugi, M.; Kitamura, T.; Yamamoto, T.; Asakura, M.; Fujiwara, R.; Itoh, T.; Fujii, H.; Hirono, S.
    J. Mol. Graph. Model., 2018, 79, 254-263.

    Research Papers : 2017

    The application of a specific morphinan template to the synthesis of galanthamine.
    Yamamoto, N.; Okada, T.; Harada, Y.; Kutsumura, N.; Imaide, S.; Saitoh, T.; Fujii, H.; Nagase, H.
    Tetrahedron, 2017, 73, 5751−5758.

    Deprotection of silyl ethers by using SO3H silica gel: Application to sugar, nucleoside, and alkaloid derivatives.
    Fujii, H.; Shimada, N.; Ohtawa, M.; Karaki, F.; Koshizuka, M.; Hayashida, K.; Kamimura, M.; Makino, K.; Nagamitsu, T.; Nagase, H.
    Tetrahedron, 2017, 73, 5425−5429.

    C-Homomorphinan Derivatives as Lead Compounds to Obtain Safer and More Clinically Useful Analgesics.
    Ishikawa, K.; Karaki, F.; Tayama, K.; Higashi, E.; Hirayama, S.; Itoh, K.; Fujii, H.
    Chem. Pharm. Bull., 2017, 65, 920-929.

    Reactivity of 7-Azanorbornenes in Bioorthogonal Inverse Electron-Demand Diels–Alder Reactions.
    Karaki, F.; Ohgane, K.; Imai, H.; Itoh, K.; Fujii, H.
    Eur. J. Org. Chem., 2017, 2017, 3815-3829.

    Design and synthesis of novel δ opioid receptor agonists with an azatricyclodecane skeleton for improving blood-brain barrier penetration.
    Watanabe, Y.; Hayashida, K.; Saito, D.; Takahashi, T.; Sakai, J.; Nakata, E.; Kanda, T.; Iwai, T.; Hirayama, S.; Fujii, H.; Yamakawa, T.; Nagase H.
    Bioorg. Med. Chem. Lett., 2017, 27, 3495-3498.

    Phenanthridin-6-one derivatives as the first class of non-steroidal pharmacological chaperones for Niemann-Pick disease type C1 protein.
    Fukuda, H.; Karaki, F.; Dodo, K.; Noguchi-Yachide, T.; Ishikawa, M.; Hashimoto, Y.; Ohgane, K.
    Bioorg. Med. Chem. Lett., 2017, 27, 2781-2787.

    Novel delta opioid receptor agonists with oxazatricyclodecane structure showing potent agonistic activities.
    Hayashida, K.; Hirayama, S.; Iwai, T.; Watanabe, Y.; Takahashi, T.; Sakai, J.; Nakata, E.; Yamakawa, T.; Fujii, H.; Nagase H.
    Bioorg. Med. Chem. Lett., 2017, 27, 2742-2745.

    Effects of repeated treatment with a delta opioid receptor agonist KNT-127 on hyperemotionality in olfactory-bulbectomized rats.
    Gotoh, L.; Saitoh, A.; Yamada, M.; Fujii, H.; Nagase, H.; Yamada, M.
    Behav. Brain Res., 2017, 323, 11-14.

    Design and Synthesis of Potent and Highly Selective Orexin 1 Receptor Antagonists with a Morphinan Skeleton and Their Pharmacologies.
    Nagase, H.; Yamamoto, N.; Yata, M.; Ohrui, S.; Okada, T.; Saitoh, T.; Kutsumura, N.; Nagumo, Y.; Irukayama-Tomobe, Y.; Ishikawa, Y.; Ogawa, Y.; Hirayama, S.; Kuroda, D.; Watanabe, Y.; Gouda, H.; Yanagisawa, M.
    J. Med. Chem., 2017, 60, 1018-1040.

    Hepatic dipeptidyl peptidase-4 controls pharmacokinetics of vildagliptin in vivo.
    Asakura, M.; Fukami, T.; Nakajima, M.; Fujii, H.; Atsuda, K.; Itoh, T.; Fujiwara, R.
    Drug Metab. Dispos., 2017, 4, 237.

    Research Papers : 2016

    Hepatic dipeptidyl peptidase-4 controls pharmacokinetics of vildagliptin in vivo.
    Asakura, M.; Fukami, T.; Nakajima, M.; Fujii, H.; Atsuda, K.; Itoh, T.; Fujiwara, R.
    Drug Metab. Dispos., 2017, 4, 237.

    Vildagliptin and its metabolite M20.7 induce the expression of S100A8 and S100A9 in human hepatoma HepG2 and leukemia HL-60 cells.
    Asakura, M.; Karaki, F.; Fujii, H.; Atsuda, K.; Itoh, T.; Fujiwara, R.
    Sci. Rep., 2016, 6, 35633.

    MicroRNA expression in the vildagliptin-treated two- and three-dimensional HepG2 cells.
    Yamashita, Y.; Asakura, M.; Mitsugi, R.; Fujii, H.; Nagai, K.; Atsuda, K.; Itoh, T.; Fujiwara, R.
    Drug Metab. Pharmacokinet., 2016, 31, 201−209.

    Narcolepsy-like sleep disturbance in orexin knockout mice are normalized by the 5-HT1A receptor agonist 8-OH-DPAT.
    Mori, T.; Uzawa, N.; Iwase, Y.; Masukawa, D.; Rahmadi, M.; Hirayama, S.; Hokazono, M.; Higashiyama, K.; Shioda, S.; Suzuki, T.
    Psychopharmacology, 2016, 233, 2324-2353.

    Synthesis and evaluation of novel opioid ligands with a C-homomorphinan skeleton.
    Ishikawa, K.; Mochizuki, Y.; Hirayama, S.; Nemoto, T.; Itoh, K.; Fujii, H.
    Bioorg. Med. Chem., 2016, 24, 2199-2205.

    Research Papers : 2015

    Photochemically-Induced C-C Bond Formation between Tertiary Amines and Nitrones.
    Itoh, K.; Kato, R.; Kinugawa, D.; Kamiya, H.; Kudo, R.; Hasegawa, M.; Fujii, H.; Suga, H.
    Org. Biomol. Chem., 2015, 13, 8919-8924.

    Synthesis of new opioid derivatives with a propellane skeleton and their pharmacologies: Part 5, novel pentacyclic propellane derivatives with a 6-amide side chain.
    Nakajima, R.; Yamamoto, N.; Hirayama, S.; Iwai, T.; Saitoh, A.; Nagumo, Y.; Fujii, H.; Nagase, H.
    Bioorg. Med. Chem., 2015, 25, 4890-4892.

    Investigation of 7-benzylidenenaltrexone derivatives as a novel structural antitrichomonal lead compound.
    Kutsumura, N.; Nakajima, R.; Koyama, Y.; Miyata, Y.; Saitoh, T.; Yamamoto, N.; Iwata, S; Fujii, H.; Nagase, H.
    Bioorg. Med. Chem. Lett., 2015, 23, 6271-6279.

    Design and Synthesis of Non-Peptide, Selective Orexin Receptor 2 Agonists.
    Nagahara, T.; Saitoh, T.; Kutsumura, N.; Irukayama-Tomobe, Y.; Ogawa, Y.; Kuroda, D.; Gouda, H.; Kumagai, H.; Fujii, H.; Yanagisawa, M.; Nagase, H.
    J. Med. Chem., 2015, 58, 7931-7937.

    Naltrindole derivatives with fluorinated ethyl substituents on the 17-nitrogen as δ opioid receptor inverse agonists.
    Nemoto, T.; Iihara, Y.; Hirayama, S.; Iwai, T.; Higashi, E.; Fujii, H.; Nagase, H.
    Bioorg. Med. Chem. Lett., 2015, 25, 2927-2930.

    Chiral Lewis Acid-Catalyzed Enantioselective Cycloadditions between Indoles and Cyclic Carbonyl Ylides Derived from Diazodiketone or Diazoketoester Derivatives.
    Suga, H.; Sekikawa, Y.; Misawa, S.; Kinugawa, D.; Oda, R.; Itoh, K.; Toda, Y.; Kiyono, R.
    J. Org. Chem., 2015, 80, 6687-6696.

    Dipeptidyl Peptidase-4 Greatly Contributes to the Hydrolysis of Vildagliptin in Human Liver.
    Asakura, M.; Fujii, H.; Atsuda, K.; Itoh, T.; Fujiwara, R.
    Drug Metab. Dispos., 2015, 43, 477-484.

    Generation of cycloheptynes and cyclooctynes via a sulfoxide–magnesium exchange reaction of readily synthesized 2-sulfinylcycloalkenyl triflates .
    Yoshida, S.; Karaki, F.; Uchida, K.; Hosoya, T.
    Chem. Commun., 2015, 51, 8745-8748.

    Transformation of naltrexone into mesembrane and investigation of the binding properties of its intermediate derivatives to opioid receptors.
    Konoura, K.; Fujii, H.; Imaide, S.; Gouda, H.; Hirayama, S.; Hirono, S.; Nagase, H.
    Bioorg. Med. Chem., 2015, 23, 439-448.

    Research Papers : 2014

    Design, synthesis, and structure–activity relationship of novel opioid κ receptor selective agonists: α-Iminoamide derivatives with an azabicyclo[2.2.2]octene skeleton.
    Watanabe, Y.; Kitazawa, S.; Fujii, H.; Nemoto, T.; Hirayama, S.; Iwai, T.; Gouda, H.; Hirono, S.; Nagase, H.
    Bioorg. Med. Chem. Lett., 2014, 24, 4980-4983.

    Human nitrilase-like protein does not catalyze the hydrolysis of vildagliptin.
    Asakura, M.; Nakano, M.; Hayashida, K.; Fujii, H.; Nakajima, M.; Atsuda, K.; Itoh, T.; Fujiwara, R.
    Drug Metab. Pharmacokinet., 2014, 29, 463-469.

    Synthesis of a novel universal opioid receptor agonist with the 1,3,5-trioxazatriquinane skeleton and its pharmacologies.
    Hirayama, S.; Wada, N.; Kuroda, N.; Iwai, T.; Yamaotsu, N.; Hirono, S.; Fujii, H.; Nagase, H.
    Bioorg. Med. Chem. Lett., 2014, 24, 4895-4898.

    Synthesis and Pharmacology of a Novel κ Opioid Receptor (KOR) Agonist with a 1,3,5-Trioxazatriquinane Skeleton.
    Hirayama, S.; Wada, N.; Nemoto, T.; Iwai, T.; Fujii, H.; Nagase, H.; Fujii, H.; Nagase, H.
    ACS Med. Chem. Lett., 2014, 5, 868-872.

    Novel Delta Opioid Receptor Agonists with Oxazatricyclodecane Structure.
    Fujii, H.; Hayashida, K.; Saitoh, A.; Yokoyama, A.; Hirayama, S.; Iwai, T.; Nakata, E.; Nemoto, T.; Sudo, Y.; Uezono, Y.; Yamada, M.; Nagase, H.; Fujii, H.
    ACS Med. Chem. Lett., 2014, 5, 368-372.

    Zinc-Acetic Acid Promoted Reductive Carbon-Nitrogen Bond Cleavage Reaction of α-Aminoketones.
    Ishikawa, K.; Tomatsu, M.; Nagase, H.; Fujii, H.
    Heterocycles, 2014, 88, 1051-1063.