We found previously that 7-[3-(cyclohexylmethyl)ureido]-3-{1-methyl-1
H-pyrrolo[2,3-b]pyridin-3-yl}quinoxalin-2(1
H)-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=0.05 μmol/l in CPA, 0.03 μmol/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=0.014 μmol/l in CPA, 0.007 μmol/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=0.004 μmol/l in CPA, 0.0008 μmol/l in APA, KDR: IC
50=0.008 μmol/l in APA). Herein we report a new and convenient synthetic method for this series of derivatives and its SAR study.
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