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.
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.
Kubo
Kazuo
K
Pharmaceutical Research and Development Laboratories, Kirin Brewery Co. Ltd., 3 Miyahara-cho, Takasaki-shi, Gunma 370-1295, Japan. ka-kubo@kirin.co.jp
Shimizu
Toshiyuki
T
Ohyama
Shin-ichi
S
Murooka
Hideko
H
Iwai
Akemi
A
Nakamura
Kazuhide
K
Hasegawa
Kazumasa
K
Kobayashi
Yoshiko
Y
Takahashi
Noriko
N
Takahashi
Kazumi
K
Kato
Shinichiro
S
Izawa
Toshio
T
Isoe
Toshiyuki
T
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
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