Design and Synthesis of Peptidomimetic Factor VIIa Inhibitors

• Shiraishi Takuya

  Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd.

• Kadono Shojiro

  Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd.

• Haramura Masayuki

  Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd.

• Kodama Hirofumi

  Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd.

• Ono Yoshiyuki

  Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd.

• Iikura Hitoshi

  Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd.

• Esaki Tohru

  Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd.

• Koga Takaki

  Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd.

• Hattori Kunihiro

  Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd.

• Watanabe Yoshiaki

  Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd.

• Sakamoto Akihisa

  Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd.

• Yoshihashi Kazutaka

  Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd.

• Kitazawa Takehisa

  Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd.

• Esaki Keiko

  Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd.

• Ohta Masateru

  Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd.

• Sato Haruhiko

  Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd.

• Kozono Toshiro

  Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd.

抄録

Selective factor VIIa-tissue factor complex (FVIIa/TF) inhibition is regarded as a promising target for developing new anticoagulant drugs. In previous reports, we described a S3 subsite found in the X-ray crystal structure of compound 2 that bound to FVIIa/soluble tissue factor (sTF). Based on the X-ray crystal structure information and with the aim of improving the inhibition activity for FVIIa/TF and selectivity against other serine proteases, we synthesized derivatives by introducing substituents at position 5 of the indole ring of compound 2. Among them, compound 16 showed high selectivity against other serine proteases. Contrary to our expectations, compound 16 did not occupy the S3-subsite; X-ray structure analysis revealed that compound 16 improved selectivity by forming hydrogen bonds with Gln217, Thr99 and Asn100.

収録刊行物

• ＣＨＥＭＩＣＡＬ　＆　ＰＨＡＲＭＡＣＥＵＴＩＣＡＬ　ＢＵＬＬＥＴＩＮ

  ＣＨＥＭＩＣＡＬ　＆　ＰＨＡＲＭＡＣＥＵＴＩＣＡＬ　ＢＵＬＬＥＴＩＮ 58 (1), 38-44, 2010

  公益社団法人 日本薬学会

キーワード

• factor VIIa
• X-ray
• 2×activated partial thromboplastin time/2×prothrombin time
• thromboembolic disorder
• peptidomimetic inhibitor

詳細情報

• CRID: 1390001204169779712
• NII論文ID: 130000140762
• DOI: 10.1248/cpb.58.38
• ISSN: 13475223
• ISSN: 00092363
• Web Site: http://www.jstage.jst.go.jp/article/cpb/58/1/58_1_38/_pdf
• 本文言語コード: en
• データソース種別:
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  • CiNii Articles
• 抄録ライセンスフラグ: 使用不可