title: Orally active 4-amino-5-diarylurea-furo[2,3-d]pyrimidine derivatives as anti-angiogenic agent inhibiting VEGFR2 and Tie-2.
abstract: 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.
authors.affiliation: GlaxoSmithKline, Tsukuba Research Laboratories, 43, Wadai, Tsukuba 300-4247, Ibaraki, Japan. yasushi.miyazaki@gsk.com
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Miyazaki
authors.forename: Jun
authors.initials: J
authors.lastname: Tang
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Maeda
authors.forename: Masato
authors.initials: M
authors.lastname: Nakano
authors.forename: Liping
authors.initials: L
authors.lastname: Wang
authors.forename: Robert T
authors.initials: RT
authors.lastname: Nolte
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Sato
authors.forename: Masaki
authors.initials: M
authors.lastname: Sugai
authors.forename: Yuji
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Anne T
authors.initials: AT
authors.lastname: Truesdale
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Hassler
authors.forename: Eldridge N
authors.initials: EN
authors.lastname: Nartey
authors.forename: Denis R
authors.initials: DR
authors.lastname: Patrick
authors.forename: Maureen L
authors.initials: ML
authors.lastname: Ho
authors.forename: Kazunori
authors.initials: K
authors.lastname: Ozawa
mesh_terms: 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*
chemical_list: 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