Orally active 4-amino-5-diarylurea-furo[2,3-d]pyrimidine derivatives as anti-angiogenic agent inhibiting VEGFR2 and Tie-2.
During our effort to develop dual VEGFR2 and Tie-2 inhibitors as anti-angiogenic agents for cancer therapy, we discovered 4-amino-5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)- aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine (8a) possessing strong inhibitory activity at both the enzyme and cellular level against VEGFR2 and Tie-2. Compound 8a demonstrated high pharmacokinetic exposure through oral administration, and showed marked tumor growth inhibition and anti-angiogenic activity in mouse HT-29 xenograft model via once-daily oral administration.
Miyazaki
Yasushi
Y
GlaxoSmithKline, Tsukuba Research Laboratories, 43, Wadai, Tsukuba 300-4247, Ibaraki, Japan. yasushi.miyazaki@gsk.com
Tang
Jun
J
Maeda
Yutaka
Y
Nakano
Masato
M
Wang
Liping
L
Nolte
Robert T
RT
Sato
Hideyuki
H
Sugai
Masaki
M
Okamoto
Yuji
Y
Truesdale
Anne T
AT
Hassler
Daniel F
DF
Nartey
Eldridge N
EN
Patrick
Denis R
DR
Ho
Maureen L
ML
Ozawa
Kazunori
K
D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D019540:Area Under Curve; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D005260:Female; D019073:HT29 Cells; D006801:Humans; D007202:Indicators and Reagents; D008297:Male; D051379:Mice; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors*; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D007202:Indicators and Reagents; D011743:Pyrimidines; D012313:RNA; D014508:Urea; D042787:Receptor, TIE-2; D040301:Vascular Endothelial Growth Factor Receptor-2