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

• Published in: Journal of medicinal chemistry 2005-03, Vol.48 (5), p.1359-1366
• Main Authors: Kubo, Kazuo, Shimizu, Toshiyuki, Ohyama, Shin-ichi, Murooka, Hideko, Iwai, Akemi, Nakamura, Kazuhide, Hasegawa, Kazumasa, Kobayashi, Yoshiko, Takahashi, Noriko, Takahashi, Kazumi, Kato, Shinichiro, Izawa, Toshio, Isoe, Toshiyuki
• Format: Article
• Language: English
• Subjects: Administration, Oral; Angiogenesis Inhibitors - chemical synthesis; Angiogenesis Inhibitors - chemistry; Angiogenesis Inhibitors - pharmacology; Animals; Antineoplastic agents; Biological and medical sciences; Cell Proliferation - drug effects; Endothelial Cells - drug effects; Endothelium, Vascular - cytology; General aspects; Humans; In Vitro Techniques; Medical sciences; Mice; Mice, Nude; Miscellaneous; Pharmacology. Drug treatments; Phenylurea Compounds - chemical synthesis; Phenylurea Compounds - chemistry; Phenylurea Compounds - pharmacology; Quinolines - chemical synthesis; Quinolines - chemistry; Quinolines - pharmacology; Rats; Structure-Activity Relationship; Umbilical Veins - cytology; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; Xenograft Model Antitumor Assays
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm030427r

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 IC50 value of 0.90 nM, and also inhibited the PDGFR family members such as PDGFRα 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.