Synthesis of 2(1H)-Quinolinone Derivatives and Their Inhibitory Activity on the Release of 12(S)-Hydroxyeicosatetraenoic Acid (12-HETE) from Platelets

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概要

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• A search for potent inhibitors of release of 12(S)-hydroxyeicosatetraenoic acid (12-HETE), which plays an important role in the pathogenesis of various circulatory disorders and arteriosclerosis, led us to 6-[4-(1-cyclohexyl-5-tetrazolyl)butoxy]-3,4-dihydro-2(1H)-quinolinone (cilostazol) and 2(1H)-quinoinone derivatives having an azole group in the side chain. Many 2(1H)-quinolilnone derivatives were synthesized and tested in vitro for the inhibitory activity in human platelets. 3,4-Dihydro-6-[3-(1-o-tolylimidazol-2-yl)sulfinylpropoxy]-2(1H)-quinolinone (5k) was found to be one of the most potent inhibitors of 12-HETE release, being more potent than esculetin. In addition, the sulfoxide 5k showed in vivo inhibitory activity on platelet adhesion in rats. Since 5k is recemic, the enantiomers were prepared and their potencies were compared in vitro and in vivo. (S)-(+)-5k had the best pharmacological profile and was selected as a candidate drug for further development. The structure-activity relationships are discussed.

• 社団法人日本薬学会の論文
• 1995-10-15

著者

• 小関 靖

  大塚製薬血栓血管研究室

• 井川 武洋

  大塚アメリカメリーランド研究所

• 木戸 勝

  Second Institute Of New Drug Research Otsuka Pharmaceutical Co. Ltd.

• 宇野 哲之

  Third Institute Of New Drug Research Otsuka Pharmaceutical Co. Ltd.

• 田村 克巳

  Third Institute Of New Drug Research Otsuka Pharmaceutical Co. Ltd.

• 小関 靖

  Third Institute of New Drug Research Otsuka Pharmaceutical Co., Ltd.,

• 古賀 康雄

  Third Institute of New Drug Research Otsuka Pharmaceutical Co., Ltd.,

• 朱 吉男

  Third Institute of New Drug Research Otsuka Pharmaceutical Co., Ltd.,

• 岡田 稔

  Third Institute of New Drug Research Otsuka Pharmaceutical Co., Ltd.,

• 井川 武洋

  Third Institute of New Drug Research Otsuka Pharmaceutical Co., Ltd.,

• 采見 フミ子

  Third Institute of New Drug Research Otsuka Pharmaceutical Co., Ltd.,

• 西 孝夫

  Third Institute of New Drug Research Otsuka Pharmaceutical Co., Ltd.,

• 西 孝夫

  Third Institute Of New Drug Research Otsuka Pharmaceutical Co. Ltd.

• 采見 フミ子

  Third Institute Of New Drug Research Otsuka Pharmaceutical Co. Ltd.

• 岡田 稔

  Third Institute Of New Drug Research Otsuka Pharmaceutical Co. Ltd.

• Koga Y

  Third Institute Of New Drug Research Otsuka Pharmaceutical Co. Ltd.

• 古賀 康雄

  Third Institute Of New Drug Research Otsuka Pharmaceutical Co. Ltd.

• Kido Masaru

  Second Institute Of New Drug Research Otsuka Pharmaceutical Co. Ltd.

• Nishi Takao

  Third Institute Of New Drug Research Otsuka Pharmaceutical Co. Ltd.

• Igawa T

  Third Institute Of New Drug Research Otsuka Pharmaceutical Co. Ltd.

• Tamura K

  Third Institute Of New Drug Research Otsuka Pharmaceutical Co. Ltd.

• 朱 吉男

  Third Institute Of New Drug Research Otsuka Pharmaceutical Co. Ltd.

• Okada Minoru

  Third Institute Of New Drug Research Otsuka Pharmaceutical Co. Ltd.

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