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Your search keyword '"Hirayama, Fukushi"' showing total 28 results
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28 results on '"Hirayama, Fukushi"'

12. Design, synthesis and biological activity of YM-60828 derivatives: potent and orally-Bioavailable factor Xa inhibitors based on naphthoanilide and naphthalensulfonanilide templates

Author

Hirayama, Fukushi, Koshio, Hiroyuki, Ishihara, Tsukasa, Watanuki, Susumu, Hachiya, Shunichiro, Kaizawa, Hiroyuki, Kuramochi, Takahiro, Katayama, Naoko, Kurihara, Hiroyuki, Taniuchi, Yuta, Sato, Kazuo, Sakai-Moritani, Yumiko, Kaku, Seiji, Kawasaki, Tomihisa, Matsumoto, Yuzo, Sakamoto, Shuichi, and Tsukamoto, Shin-ichi

Published
2002
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14. One‐Pot Synthetic Procedure for2,2′‐Disubstituted Biaryls via the Suzuki Coupling Reaction of Aryl Triflates in a Biphasic Solvent System.

Author

Miura, Masanori, Koike, Takanori, Ishihara, Tsukasa, Hirayama, Fukushi, Sakamoto, Shuichi, Okada, Minoru, Ohta, Mitsuaki, and Tsukamoto, Shin‐ichi

Subjects
CHEMICAL reactions, ORGANIC synthesis, ASYMMETRIC synthesis, LIGANDS (Chemistry), AROMATIC compounds, SOLUTION (Chemistry)
Abstract

A one‐pot synthetic procedure for 2,2′‐disubstituted biaryls was developed via a Suzuki cross‐coupling reaction of aryl triflates in a biphasic solvent system. The effects of various bases and solvents were investigated. Results showed that the Na2CO3–toluene/H2O combination gave the highest yields. [ABSTRACT FROM AUTHOR]

Published
2006
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26. AKR-501 (YM477) in combination with thrombopoietin enhances human megakaryocytopoiesis

Author

Fukushima-Shintani, Mari, Suzuki, Ken-ichi, Iwatsuki, Yoshiyuki, Abe, Masaki, Sugasawa, Keizo, Hirayama, Fukushi, and Kawasaki, Tomihisa

Subjects
*CELLS, *BONE marrow cells, *COLONIZATION, *IMPERIALISM
Abstract

Objective: AKR-501 (YM477) is an orally active thrombopoietin (TPO) receptor agonist that mimics the biological effect of TPO in vitro and in vivo. Here, we report that AKR-501 in combination with TPO has additive effect on megakaryocytopoiesis. Materials and Methods: Granulocyte colony-stimulating factor–mobilized human peripheral blood CD34+ cells were cultured with AKR-501, TPO, or a combination of the two in serum-free liquid culture system. The numbers of hematopoietic progenitor cells, megakaryocytic progenitor cells, and megakaryocytes were measured using flow cytometry. Further, the effect of AKR-501 on TPO binding to TPO receptor was examined. Results: Both AKR-501 and TPO alone increased the number of megakaryocytes, and the maximum activities of AKR-501 and TPO were similar. Interestingly, in the presence of TPO concentrations producing maximal stimulation, the addition of AKR-501 increased the number of megakaryocytes to about 200% of that generated with TPO only. In the time course experiment, the combination of AKR-501 and TPO augmented the numbers of hematopoietic progenitor cells and colony-forming unit in culture in the early stages. Thus, the combination of AKR-501 and TPO enhanced not only the differentiation into megakaryocytes, but also the expansion of human hematopoietic progenitor cells. Further, AKR-501 did not inhibit TPO binding to the TPO receptor. This result indicated the possibility that AKR-501 and TPO may act simultaneously on the TPO receptor, and this could be responsible for their additive effect of on megakaryocytopoiesis. Conclusions: This study suggests that AKR-501 would be useful for the treatment of thrombocytopenia even at high plasma levels of endogenous TPO following chemotherapy. [Copyright &y& Elsevier]

Published
2008
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27. Discovery of N-[2-hydroxy-6-(4-methoxybenzamido)phenyl]-4- (4-methyl-1,4-diazepan-1-yl)benzamide (darexaban, YM150) as a potent and orally available factor Xa inhibitor.

Author

Hirayama F, Koshio H, Ishihara T, Hachiya S, Sugasawa K, Koga Y, Seki N, Shiraki R, Shigenaga T, Iwatsuki Y, Moritani Y, Mori K, Kadokura T, Kawasaki T, Matsumoto Y, Sakamoto S, and Tsukamoto S

Subjects
Administration, Oral, Animals, Anticoagulants chemical synthesis, Anticoagulants pharmacokinetics, Anticoagulants pharmacology, Azepines chemistry, Azepines pharmacology, Benzamides chemistry, Benzamides pharmacology, Biological Availability, Catalytic Domain, Factor Xa chemistry, Fibrinolytic Agents chemistry, Fibrinolytic Agents pharmacology, Glucuronides metabolism, Humans, In Vitro Techniques, Male, Mice, Mice, Inbred ICR, Microsomes, Liver metabolism, Models, Molecular, Rats, Rats, Inbred F344, Structure-Activity Relationship, Azepines chemical synthesis, Benzamides chemical synthesis, Factor Xa Inhibitors, Fibrinolytic Agents chemical synthesis
Abstract

Inhibitors of factor Xa (FXa), a crucial serine protease in the coagulation cascade, have attracted a great deal of attention as a target for developing antithrombotic agents. We previously reported findings from our optimization study of a high-throughput screening (HTS) derived lead compound 1a that resulted in the discovery of potent amidine-containing FXa inhibitors represented by compound 2. We also conducted an alternative optimization study of 1a without incorporating a strong basic amidine group, which generally has an adverse effect on the pharmacokinetic profile after oral administration. Replacement of 4-methoxybenzene with a 1,4-benzodiazepine structure and introduction of a hydroxy group at the central benzene led to the discovery of the potent and orally effective factor Xa inhibitor 14i (darexaban, YM150). Subsequent extensive study revealed a unique aspect to the pharmacokinetic profile of this compound, wherein the hydroxy moiety of 14i is rapidly transformed into its glucuronide conjugate 16 (YM-222714) as an active metabolite after oral administration and it plays a major role in expression of potent anticoagulant activity in plasma. The distinctive, potent activity of inhibitor 14i after oral dosing was explained by this unique pharmacokinetic profile and its favorable membrane permeability. Compound 14i is currently undergoing clinical development for prevention and treatment of thromboembolic diseases.

Published
2011
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28. An easy access to 7-methyl-2-naphthalenecarbonitrile.

Author

Koshio H, Ishihara T, Yamada H, Hirayama F, Matsumoto Y, and Yanagisawa I

Subjects
Benzaldehydes, Chromatography, Thin Layer, Heterocyclic Compounds chemical synthesis, Magnetic Resonance Spectroscopy, Piperidines chemical synthesis, Spectrophotometry, Ultraviolet, Anticoagulants chemical synthesis, Naphthalenes chemical synthesis, Nitriles chemical synthesis
Abstract

A practical and cost-effective procedure has been developed for the synthesis of 7-methyl-2-naphthalenecarbonitrile, the precursor of the anticoagulant agents YM-60828 or YM-96765. This new route generates the key intermediate in only two steps from readily available 3-cyanopropionaldehyde dimethyl acetal and m-tolualdehyde, without requiring chromatographic purification. The synthesis involves condensation of the cyano derivative with the aldehyde and subsequent cyclodehydration.

Published
2005
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