Potent Platelet-Derived Growth Factor-β Receptor (PDGF-βR) Inhibitors : Synthesis and Structure-Activity Relationships of 7-[3-(Cyclohexylmethyl)ureido]-3-{1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl}quinoxalin-2(1H)-one Derivatives
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概要
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We found previously that 7-[3-(cyclohexylmethyl)ureido]-3-{1-methyl-1H-pyrrolo[2,3-blpyridin-3-yl}quinoxalin-2(1H)-one (7d-6) has considerable potency as a PDGF inhibitor. This compound showed potent inhibitory activity in a PDGF-induced CPA (Cell Proliferation Assay) and APA (Auto-Phosphorylation Assay) (IC_<50>=0.05μmol/l in CPA, 0.03μmol/l in APA). Therefore, we tried to develop a novel and effective PDGF-βR inhibitor by optimizing a series of its derivatives. We found that trifluoroacetic acid (TFA)-catalyzed coupling of pyrrolo[2,3-b]pyridines with quinoxalin-2-ones proceeded efficiently under mild oxidation condition with manganese(IV) oxide (MnO_2) in situ, so this method was applied to prepare a series of derivatives. Results of in vitro screening of newly synthesized derivatives identified compound 7d-9 as having potent (IC_<50>=0.014μmol/l in CPA, 0.007μmol/l in APA) and selective [IC_<50> values against vascular endothelial growth factor receptor 2 (VEGFR2, kinase domain region, KDR), epidermal growth factor receptor (EGFR), c-Met (hepatocyte growth factor receptor) and insulin growth factor I receptor (IGF-IR)/IC_<50> against PDGFR were each >1000] inhibitory activity. Moreover, in this series of derivatives, 7b-2 showed potent inhibitory activity toward both PDGF- and VEGF-induced signaling (PDGFR: IC_<50>=0.004μmol/l in CPA, 0.0008μmol/l in APA, KDR: IC_<50>=0.008μmol/l in APA). Herein we report a new and convenient synthetic method for this series of derivatives and its SAR study.
- 社団法人日本薬学会の論文
- 2007-02-01
著者
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竹田 秀一
ツムラ研究本部
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MIYAMOTO Ken-ichi
Department of Pharmacology and Pharmaceutics, Graduate School of Natural Science and Technology, Kan
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ABURADA Masaki
Research Division, Tsumura & Co.
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油田 正樹
Res. Inst. Of Pharmaceutical Sciences Musashino Univ.
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油田 正樹
Medicinal Evaluation Laboratory Tsumura Research Institute
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Aburada M
Fac. Of Pharmacy Musashino Univ.
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Aburada M
Tsumura Research Inst. Pharmacology Ibaraki Jpn
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MORI Yoshikazu
R & D Division, Tsumura & Co.
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AOKI Katsuyuki
R & D Division, Tsumura & Co.
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TAKEDA Shuichi
R & D Division, Tsumura & Co.
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OBATA Tatsuhiro
R & D Division, Tsumura & Co.
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YAMAZAKI Yosuke
R & D Division, Tsumura & Co.
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HIROKAWA Hiroko
R & D Division, Tsumura & Co.
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KOSEKI Jun-ichi
R & D Division, Tsumura & Co.
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HATTORI Tomohisa
R & D Division, Tsumura & Co.
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NIITSU Kazuaki
R & D Division, Tsumura & Co.
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Aoki Katsuyuki
R & D Division Tsumura & Co.:department Of Clinical Pharmacy Graduate School Of Natural Scie
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Yamazaki Yosuke
R & D Division Tsumura & Co.
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Niitsu Kazuaki
R & D Division Tsumura & Co.
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Miyamoto Ken-ichi
金沢大学 薬学部臨床薬物情報
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Miyamoto Ken-ichi
Dep. Of Clinical Pharmacy Graduate School Of Natural Sci. And Technol. Kanazawa Univ.
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Hirokawa Hiroko
R & D Division Tsumura & Co.
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Hattori Tomohisa
Tsumura & Co. Tsumura Res. Laboratories
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竹田 秀一
Tsumura & Co. Tsumura Res. Laboratories
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油田 正樹
ツムラ研究本部 医薬評価研究所
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Miyaamoto Ken-ichi
Department Of Medical Informatics Graduate School Of Medical Science Kanazawa University
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Mizuhara Yasuharu
Medicinal Evaluation Laboratory Tsumura & Co.:department Of Medicinal Informatics Graduate Schoo
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Miyamoto K
Department Of Hospital Pharmacy School Of Medicine Kanazawa University
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Miyamoto K
Kanazawa Univ. Hospital Ishikawa Jpn
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Takeda Shuichi
Department Of Drug Metabolism & Disposition Tsumura Research Institute Tsumura & Co.
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Koseki Jun-ichi
R & D Division Tsumura & Co.
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Aburada Masaki
Musashino Univ. Tokyo Jpn
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Miyamoto Ken'ichi
Hospital Pharmacy School Of Medicine Kanazawa University
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Miyamoto Ken-ichi
Department Of Applied Pharmacology Faculty Of Pharmaceutical Sciences Hokuriku University
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Takeda Shuichi
Tsumura & Co. Tsumura Research Laboratories
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Mori Yoshikazu
R & D Division Tsumura & Co.:department Of Clinical Pharmacy Graduate School Of Natural Science And Technology Kanazawa University
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Miyamoto Ken-ichi
Department of Clinical Pharmacy, Graduate School of Natural Science and Technology, Kanazawa University
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