title: Novel potent orally active selective VEGFR-2 tyrosine kinase inhibitors: synthesis, structure-activity relationships, and antitumor activities of N-phenyl-N'-{4-(4-quinolyloxy)phenyl}ureas.
abstract: N-Phenyl-N'-{4-(4-quinolyloxy)phenyl}ureas were found to be a novel class of potent inhibitors for the vascular endothelial growth factor receptor 2 (VEGFR-2) tyrosine kinase through synthetic modifications of a lead compound and structure-activity relationship studies. A representative compound 6ab, termed Ki8751, inhibited VEGFR-2 phosphorylation at an IC(50) value of 0.90 nM, and also inhibited the PDGFR family members such as PDGFRalpha and c-Kit at 67 nM and 40 nM, respectively. However, 6ab did not have any inhibitory activity against other kinases such as EGFR, HGFR, InsulinR and others even at 10000 nM. 6ab suppressed the growth of the VEGF-stimulated human umbilical vein endothelial cell (HUVEC) on a nanomolar level. 6ab showed significant antitumor activity against five human tumor xenografts such as GL07 (glioma), St-4 (stomach carcinoma), LC6 (lung carcinoma), DLD-1 (colon carcinoma) and A375 (melanoma) in nude mice and also showed complete tumor growth inhibition with the LC-6 xenograft in nude rats following oral administration once a day for 14 days at 5 mg/kg without any body weight loss.
authors.affiliation: Pharmaceutical Research and Development Laboratories, Kirin Brewery Co. Ltd., 3 Miyahara-cho, Takasaki-shi, Gunma 370-1295, Japan. ka-kubo@kirin.co.jp
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kubo
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Shimizu
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Ohyama
authors.forename: Hideko
authors.initials: H
authors.lastname: Murooka
authors.forename: Akemi
authors.initials: A
authors.lastname: Iwai
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Nakamura
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Hasegawa
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Noriko
authors.initials: N
authors.lastname: Takahashi
authors.forename: Kazumi
authors.initials: K
authors.lastname: Takahashi
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Kato
authors.forename: Toshio
authors.initials: T
authors.lastname: Izawa
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Isoe
mesh_terms: D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008819:Mice, Nude; D010671:Phenylurea Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D014471:Umbilical Veins / Q000166:cytology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; C499138:N-(2,4-difluorophenyl)-N'-(4-((6,7-dimethoxy-4-quinolyl)oxy)-2-fluorophenyl)urea; D010671:Phenylurea Compounds; D011804:Quinolines; D040301:Vascular Endothelial Growth Factor Receptor-2