Takenori Ishizawa
Chugai Pharmaceutical Co.
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Featured researches published by Takenori Ishizawa.
Bioorganic & Medicinal Chemistry | 2009
Akie Homma; Haruhiko Sato; Akira Okamachi; Takashi Emura; Takenori Ishizawa; Tatsuya Kato; Tetsu Matsuura; Shigeo Sato; Tatsuya Tamura; Yoshinobu Higuchi; Tomoyuki Watanabe; Hidetomo Kitamura; Kentaro Asanuma; Tadao Yamazaki; Masahisa Ikemi; Hironoshin Kitagawa; Tadashi Morikawa; Hitoshi Ikeya; Kazuaki Maeda; Koichi Takahashi; Kenji Nohmi; Noriyuki Izutani; Makoto Kanda; Ryochi Suzuki
Hyaluronic acid (HA) provides synovial fluid viscoelasticity and has a lubricating effect. Injections of HA preparations into the knee joint are widely used as osteoarthritis therapy. The current HA products reduce pain but do not fully control inflammation. Oral methotrexate (MTX) has anti-inflammatory efficacy but is associated with severe adverse events. Based on the rationale that a conjugation of HA and MTX would combine the efficacy of the two clinically evaluated agents and avoid the risks of MTX alone, we designed HA-MTX conjugates in which the MTX connects with the HA through peptides susceptible to cleavage by lysosomal enzymes. Intra-articular injection of our HA-MTX conjugate (conjugate 4) produced a significant reduction of the knee swelling in antigen-induced arthritis rat, whereas free MTX, HA or a mixture of HA and MTX showed no or marginal effects on the model. The efficacy of conjugate 4 was almost the same as that of MTX oral treatment. Conjugate 4 has potential as a compound for the treatment of osteoarthritis.
Bioorganic & Medicinal Chemistry Letters | 1993
Hiroshi Koga; Masateru Ohta; Haruhiko Sato; Takenori Ishizawa; Nabata Hiroyuki
Abstract A pharmacophore model which explains rationally structure-activity relationships of chemically diverse potent K + channel openers, has been constructed. Potent benzopyran derivatives with thioamide, amide, and ( N -cyano)amidine groupa at the 4-position have been designed using the model.
Bioorganic & Medicinal Chemistry | 2010
Akie Homma; Haruhiko Sato; Tatsuya Tamura; Akira Okamachi; Takashi Emura; Takenori Ishizawa; Tatsuya Kato; Tetsu Matsuura; Shigeo Sato; Yoshinobu Higuchi; Tomoyuki Watanabe; Hidetomo Kitamura; Kentaro Asanuma; Tadao Yamazaki; Masahisa Ikemi; Hironoshin Kitagawa; Tadashi Morikawa; Hitoshi Ikeya; Kazuaki Maeda; Koichi Takahashi; Kenji Nohmi; Noriyuki Izutani; Makoto Kanda; Ryohchi Suzuki
We previously reported that a conjugate of hyaluronic acid (HA) and methotrexate (MTX) could be a prototype for future osteoarthritis drugs having the efficacy of the two clinically validated agents but with a reduced risk of the systemic side effects of MTX by using HA as the drug delivery carrier. To identify a clinical candidate, we attempted optimization of a lead, conjugate 1. Initially, in fragmentation experiments with cathepsins, we optimized the peptide part of HA-MTX conjugates to be simpler and more susceptible to enzymatic cleavage. Then we optimized the peptide, the linker, the molecular weight, and the binding ratio of the MTX of the conjugates to inhibit proliferation of human fibroblast-like synoviocytes in vitro and knee swelling in rat antigen-induced monoarthritis in vivo. Consequently, we found conjugate 30 (DK226) to be a candidate drug for the treatment of osteoarthritis.
Bioorganic & Medicinal Chemistry Letters | 1993
Hiroshi Koga; Haruhiko Sato; Takenori Ishizawa; Kuromaru Kiyonori; Nabata Hiroyuki; Imagawa Jun-ichi; Shoshin Yoshida; Izumi Sugo
N-Cyano-2,2-dimethyl-6-nitro-2H-1-benzopyran-4-carboxamidines have been synthesized. Some of these compounds exhibited selective activity for guinea pig trachealis.
Bioorganic & Medicinal Chemistry | 2000
Naoki Taka; Hiroshi Koga; Haruhiko Sato; Takenori Ishizawa; Tadakatsu Takahashi; Jun-ichi Imagawa
In the course of our study to find an ideal antihypertensive potassium channel opener (KCO), N-(2-cyanoethyl)-2,2-bis(fluoromethyl)-6-pentafluoroethyl-2H-1-ben zopyran-4-carboxamide (13f, KC-515) showed a highly potent, slow and long-lasting antihypertensive effect with reduced reflex tachycardia, together with the beneficial effects of KCO such as improvement in lipid metabolism. These profiles identify KC-515 as a potential candidate. In conscious spontaneously hypertensive rats (SHR), the onset of the hypotensive effect of KC-515 (13f) was gradual and the maximum response was attained at around 6 h after dosing. The duration of action was over 18 h for 0.1 mg/kg. When administered to Zucker rats for 2 weeks with 0.03-0.3 mg/kg po range in the antihypertensive doses in hypertensive rat models, KC-515 (13f) significantly and dose-dependently reduced serum triglycerides to less than 70% of control without affecting total cholesterol.
Bioorganic & Medicinal Chemistry Letters | 1993
Hiroshi Koga; Haruhiko Sato; Takenori Ishizawa; Kiyonori Kuromaru; Toshihiko Makino; Naoki Taka; Tadakatsu Takahashi; Tsutomu Sato; Hiroyuki Nabata
Abstract N -Substituted benzopyran-4-carboxamides 5 have been synthesized. Some of these compounds exhibited potent vasorelaxant activity.
Bioorganic & Medicinal Chemistry Letters | 1993
Hiroshi Koga; Haruhiko Sato; Jun-ichi Imagawa; Takenori Ishizawa; Shohshin Yoshida; Izumi Sugo; Naoki Taka; Tadakatsu Takahashi; Hiroyuki Nabata
Abstract Synthesis and antihypertensive activity of KC-399 (5) have been described. KC-399 (5) showed a highly potent, slow and long-lasting antihypertensive effect with reduced reflex tachycardia.
Bioorganic & Medicinal Chemistry Letters | 1993
Takenori Ishizawa; Hiroshi Koga; Masateru Ohta; Haruhiko Sato; Toshihiko Makino; Kiyonori Kuromaru; Naoki Taka; Tadakatsu Takahashi; Tsutomu Sato; Hiroyuki Nabata
Abstract QSAR study of 6-substituted benzopyran-4-carbothioamides 1 showed that vasorelaxant activity is linearly correlated with the electronic parameter (σ m ) and parabolically correlated with steric ( L ) and hydrophobic (π) parameters of the 6-substituent.
Tetrahedron Letters | 1995
Hiroshi Koga; Haruhiko Sato; Takenori Ishizawa; Naoki Taka; Tadakatsu Takahashi
Abstract Key intermediates benzopyran-4-carboxylic acids of an important class of potassium channel openers benzopyran-4-amides have been synthesized via palladium-catalyzed hydroxycarbonylation.
Bioorganic & Medicinal Chemistry Letters | 1995
Haruhiko Sato; Hiroshi Koga; Takenori Ishizawa; Toshihiko Makino; Naoki Taka; Tadakatsu Takahashi; Hiroyuki Nabata
Abstract Synthesis and vasorelaxant activity of 2-fluoroalkyl-6-nitro-2 H -1-benzopyran-4-carbothioamides 4 and 6 and -carboxamides 5 and 7 are described. Potent smooth muscle relaxant activity was displayed by 6c .