Potent platelet-derived growth factor-beta receptor (PDGF-betaR) 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.
We found previously that 7-[3-(cyclohexylmethyl)ureido]-3-{1-methyl-1H-pyrrolo[2,3-b]pyridin-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) (IC50 = 0.05 micromol/l in CPA, 0.03 micromol/l in APA). Therefore, we tried to develop a novel and effective PDGF-betaR 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 (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 7d-9 as having potent (IC50 = 0.014 micromol/l in CPA, 0.007 micromol/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, 7b-2 showed potent inhibitory activity toward both PDGF- and VEGF-induced signaling (PDGFR: IC50 = 0.004 micromol/l in CPA, 0.0008 micromol/l in APA, KDR: IC50 = 0.008 micromol/l in APA). Herein we report a new and convenient synthetic method for this series of derivatives and its SAR study.
Aoki
Katsuyuki
K
R & D Division, Tsumura & Co., Ibaraki, Japan. aoki_katsuyuki@mail.tsumura.co.jp
Obata
Tatsuhiro
T
Yamazaki
Yosuke
Y
Mori
Yoshikazu
Y
Hirokawa
Hiroko
H
Koseki
Jun-Ichi
J
Hattori
Tomohisa
T
Niitsu
Kazuaki
K
Takeda
Shuichi
S
Aburada
Masaki
M
Miyamoto
Ken-ichi
K
D002384:Catalysis; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D066246:ErbB Receptors / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D017895:Manganese Compounds / Q000737:chemistry; D010084:Oxidation-Reduction; D010087:Oxides / Q000737:chemistry; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000494:pharmacology*; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014269:Trifluoroacetic Acid / Q000737:chemistry
C518849:7-(3-(cyclohexylmethyl)ureido)-3-(1-methyl-1H-pyrrolo(2,3-b)pyridin-3-yl)quinoxalin-2(1H)-one; D004791:Enzyme Inhibitors; D017895:Manganese Compounds; D010087:Oxides; D011810:Quinoxalines; C027424:manganese oxide; D017228:Hepatocyte Growth Factor; D014269:Trifluoroacetic Acid; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D017526:Receptor, IGF Type 1; D020797:Receptor, Platelet-Derived Growth Factor beta