Aoki, Katsuyuki; Obata, Tatsuhiro; Yamazaki, Yosuke; Mori, Yoshikazu; Hirokawa, Hiroko; Koseki, Jun-ichi; Hattori, Tomohisa; Niitsu, Kazuaki; Takeda, Shuichi; Aburada, Masaki; Miyamoto, Ken-ichi published the artcile< 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>, Category: quinoxaline, the main research area is pyrrolopyridinylquinoxalinone preparation platelet derived growth factor receptor inhibitor.
The authors found previously that 7-[3-(cyclohexylmethyl)ureido]-3-{1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl}quinoxalin-2(1H)-one 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) (IC50 = 0.05 μmol/l in CPA, 0.03 μmol/l in APA). Therefore, the authors tried to develop a novel and effective PDGF-βR inhibitor by optimizing a series of its derivatives The authors 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 (MnO2) in situ, so this method was applied to prepare a series of derivatives Results of in vitro screening of newly synthesized derivatives identified compound I (R = pentyl) as having potent (IC50 = 0.014 μmol/l in CPA, 0.007 μmol/l in APA) and selective [IC50 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)/IC50 against PDGFR were each >1000] inhibitory activity. Moreover, in this series of derivatives, 7-[3-(cyclohexylmethyl)thioureido]-3-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)quinoxalin-2(1H)-one showed potent inhibitory activity toward both PDGF- and VEGF-induced signaling (PDGFR: IC50 = 0.004 μmol/l in CPA, 0.0008 μmol/l in APA, KDR: IC50 = 0.008 μmol/l in APA). Herein, the authors report a new and convenient synthetic method for this series of derivatives and its SAR study.
Chemical & Pharmaceutical Bulletin published new progress about Platelet-derived growth factor receptor β Role: BSU (Biological Study, Unclassified), BIOL (Biological Study). 89898-96-4 belongs to class quinoxaline, and the molecular formula is C8H5N3O3, Category: quinoxaline.
Referemce:
Quinoxaline – Wikipedia,
Quinoxaline | C8H6N2 | ChemSpider