Preparation and Pharmacological Evaluation of Novel Glycoprotein (Gp) IIb/IIIa Antagonists. 2. Condensed Heterocyclic Derivatives

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概要

• 論文の詳細を見る

• A novel series of platelet receptor glycoprotein (Gp) IIb/IIIa antagonists with condensed heterocycles as their basic core was synthesized. In an in vitro assay, trans-4-(5-amidinobanzofuran-2-carboxamido)cyclohexyloxyacetic acid 17e and trans-3-[4-(5-amidinobanzofuran-2-carboxamido)cyclohexyl]propionic acid 17f produced marked inhibitions with IC_<50> values of 0.018 and 0.006 μM, respectively in a human platelet adenosin-5'-diphospate (ADP)-induced aggregation assay; they also exhibited a wide spectrum of inhibition toward major aggregation agonists (ADP, collagen, thrombin, PMA (tumor promoter) and arachidonic acid). These compounds were >2-3 orders of magnitude more effective in inhibiting platelet aggregation than human umbilical vein endothelial cell (HUVEC) binding. The oral administration of 10 mg/kg of either 17e and 17f to guinea pig, resulted in a 60% inhibition of ex vivo platelet aggregation after 5 h. Oral administration of ethyl trans-4-(5-amidinobenzofuran-2-carboxamido)cyclohexyloxyacetate 18e (10 mg/kg) resulted in 80% inhibition of platelet aggregation in dogs for 6 h after oral administration with a return to baseline by 24 h. Ethyl trans-3-[4-(5-amidinobenzofuran-2-carboxamido)cyclohexyl]propionate 18f (AR0598) produced 80% inhibition for 5 h after oral administration. Prodrug 18e showed a good profile in dogs with a long duration of action. 18e (AR0510) was selected as suitable clinical candidate for development as an orally active antithrombotic agent.

• 公益社団法人日本薬学会の論文
• 1999-12-15

著者

• Isobe Y

  Research Division Discovery Research Laboratories Ii Sumitomo Pharmaceuticals Co. Ltd.

• Fukaya C

  Yoshitomi Pharmaceutical Ind. Ltd. Osaka Jpn

• Fukaya Chikara

  Quality Control Production Division Yoshitomi Pharmaceutical Industries Ltd.

• Yoshida Tomohiro

  Exploratory Research Ii Drug Discovery Laboratories Yoshitomi Pharmaceutical Industries Ltd.

• Nakamura Norifumi

  President's Office Yoshitomi Pharmaceutical Industries Ltd.

• Nakamura Norihiro

  Department Of Biological Sciences Graduate School Of Science Osaka University

• 五十部 穣

  Research Center Sumitomo Pharmaceuticals Co. Ltd.

• Inoue Y

  Department Of Pharmacokinetics Kyoto Pharmaceutical University

• MAEDA Kazuhiro

  Exploratory Research II Drug Discovery Laboratories, Yoshitomi Pharmaceutical Industries, Ltd.,

• KOSAKA Keigo

  Enabling Technologies, Drug Discovery Laboratories, Yoshitomi Pharmaceutical Industries, Ltd.,

• INOUE Yoshihisa

  Enabling Technologies, Drug Discovery Laboratories, Yoshitomi Pharmaceutical Industries, Ltd.,

• IMADA Teruaki

  Exploratory Research II Drug Discovery Laboratories, Yoshitomi Pharmaceutical Industries, Ltd.,

• Kosaka K

  Beauty Care Products Division Health Care Business Group Nagase & Co. Ltd.

• Imada T

  Mitsubishi Pharma Corp. Yokohama Jpn

• Inoue Y

  Osaka Univ. Osaka Jpn

• Yoshida T

  Hakodate Institute Of National College Of Technology

• Ono Shin'ichiro

  Exploratory Research Ii Drug Discovery Laboratories Yoshitomi Pharmaceutical Industries Ltd.

• Maeda Kazuhiro

  Exploratory Research Ii Drug Discovery Laboratories Yoshitomi Pharmaceutical Industries Ltd.

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