Synthesis and Biological Activity of Novel 2-(α-Alkoxyimino)benzylpyridine Derivatives as K^+ Channel Openers
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概要
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The search for novel K^+ channel openers with a non-benzopyran skeleton, unlike cromakalim, led to the discovery of a new series of (Z)-2-(α-alkoxyimino)benzylpyridine derivatives. Synthesis was achieved by using a (Z)-dominant condensation reaction of benzoylpyridines with O-alkylhydroxylamines, followed by m-chloroperbenzoic acid (m-CPBA) oxidation. The compounds were tested for thier vasorelaxant activity in tetraethylammonium chloride (TEA) and BaCl_2- and high KCl-induced contration of rat aorta to identify potential K^+ channel openers, and also for their effects of the coronary blood flow (CBF) after intracoronary injection in anesthetized dogs. A large number of the 2-(α-alkoxyimino)benzylpyridines strongly inhibited TEA and BaCl_2-induced contraction, had no effect on 80 mM KCl-induced contraction, and increased the CBF to more than 200% of the basal flow at 10-30 μg/dog. In particular, (Z)-2-[5-bromo-α-(tert-butoxyimino)-4-fluoro-2-hydroxybenzyl]-3-hydroxypyridine 1-oxide (7d) showed highly potent vasorelaxant activity (EC_<50>=0.28 μM) comparable to that of levcromakalim (EC_<50>=0.17 μM), and gave a significantly longer-lasting increase (T_<1/2>=30 min) in the CBF compared to levromakalim, nicorandil, nitroglycerin, or diltiazem (T_<1/2>=5.2,0.9,0.4,and 2.2 min, respectively). It also exhibited a stable and long-lasting hypotensive effect (over 7 h) upon oral administration of 1 mg/kg in spontaneously hypertensive rats (SHRs).
- 社団法人日本薬学会の論文
- 1997-12-15
著者
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渡辺 敏子
School Of Pharmaceutical Sciences Toho University
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YAMAMOTO Shinobu
Showa College of Pharmaceutical Sciences
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Yamamoto Shuhei
Department Of Chemistry Graduate School Of Science Osaka City University
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山本 晋
Faculty Of Pharmaceutical Sciences Osaka University
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Watanabe Toshifumi
Pharmaceutical Research Laboratories Ii Pharmaceutical Research Division Takeda Chemical Industries
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MAEKAWA Tuyshi
Pharmaceutical Research Laboratories II, Pharmaceutical Research Division, Takeda Chemical Industrie
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YAMAMOTO Satoshi
Pharmaceutical Research Laboratories II, Pharmaceutical Research Division, Takeda Chemical Industrie
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IGATA Yumiko
Pharmaceutical Research Laboratories II, Pharmaceutical Research Division, Takeda Chemical Industrie
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IKEDA Shota
Pharmaceutical Research Laboratories II, Pharmaceutical Research Division, Takeda Chemical Industrie
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SHIRAISHI Mitsuru
Pharmaceutical Research Laboratories II, Pharmaceutical Research Division, Takeda Chemical Industrie
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Watanabe T
Chiba Univ. Chiba Jpn
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Watanabe Toshiko
Faculty Of Pharmaceutical Sciences Chiba University
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Watanabe Toshiko
Graduate School Of Pharmaceutical Sciences Chiba University
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Shiraishi Mitsuru
Medicinal Chemistry Research Laboratories Pharmaceutical Research Division Takeda Chemical Industrie
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Shiraishi Mitsuru
Pharmaceutical Research Laboratories Ii Takeda Chemical Industries Ltd.
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Shiraishi Mitsuru
Pharmaceutical Research Laboratories Ii Pharmaceutical Research Division Takeda Chemical Industries
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Watanabe Toshihiro
Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co. Ltd.
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Watanabe Toshifumi
Pharmaceutical Research Division Takeda Chemical Industries Ltd.
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Ikeda Shota
Pharmaceutical Research Laboratories Ii Pharmaceutical Research Division Takeda Chemical Industries
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Igata Yumiko
Pharmaceutical Research Laboratories Ii Pharmaceutical Research Division Takeda Chemical Industries
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Maekawa Tuyshi
Pharmaceutical Research Laboratories Ii Pharmaceutical Research Division Takeda Chemical Industries
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Yamamoto Shozo
Department Of Biochemistry Tokushima University School Of Medicine
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Shiraishi M
Medicinal Chemistry Research Laboratories Pharmaceutical Research Division Takeda Chemical Industrie
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Maekawa Tsuyoshi
Pharmaceutical Research Laboratories II, Pharmaceutical Research Division, Takeda Chemical Industries, Ltd.,
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