Novel 4-amino-furo[2,3-d]pyrimidines as Tie-2 and VEGFR2 dual inhibitors.
A novel class of furo[2,3-d]pyrimidines has been discovered as potent dual inhibitors of Tie-2 and VEGFR2 receptor tyrosine kinases (TK) and a diarylurea moiety at 5-position shows remarkably enhanced activity against both enzymes. One of the most active compounds, 4-amino-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)amino-carbonylamino)phenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine (7k) is <3 nM on both TK receptors and the activity is rationalized based on the X-ray crystal structure.
Miyazaki
Yasushi
Y
GlaxoSmithKline K.K., Tsukuba Research Laboratories, 43, Wadai, Tsukuba 300-4247, Ibaraki, Japan. yasushi.miyazaki@gsk.com
Matsunaga
Shinichiro
S
Tang
Jun
J
Maeda
Yutaka
Y
Nakano
Masato
M
Philippe
Rocher J
RJ
Shibahara
Megumi
M
Liu
Wei
W
Sato
Hideyuki
H
Wang
Liping
L
Nolte
Robert T
RT
D016475:3T3 Cells; D000818:Animals; D001665:Binding Sites; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D011487:Protein Conformation; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D014162:Transfection; D014471:Umbilical Veins; D014508:Urea / Q000031:analogs & derivatives; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors / Q000737:chemistry; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry
D011743:Pyrimidines; D014508:Urea; D042787:Receptor, TIE-2; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2