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
- 15 February 2005
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 48 (5), 1359-1366
- https://doi.org/10.1021/jm030427r
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 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.Keywords
This publication has 12 references indexed in Scilit:
- Novel 4-Anilinoquinazolines with C-7 Basic Side Chains: Design and Structure Activity Relationship of a Series of Potent, Orally Active, VEGF Receptor Tyrosine Kinase InhibitorsJournal of Medicinal Chemistry, 2002
- Protein kinase inhibitors: emerging pharmacophores 1997 - 2000Expert Opinion on Therapeutic Patents, 2001
- Design and Structure−Activity Relationship of a New Class of Potent VEGF Receptor Tyrosine Kinase InhibitorsJournal of Medicinal Chemistry, 1999
- Effects of Angiogenesis Inhibitors on Multistage Carcinogenesis in MiceScience, 1999
- Selective Inhibition of Platelet-Derived Growth Factor (PDGF) Receptor Autophosphorylation and PDGF-Mediated Cellular Events by a Quinoline DerivativeExperimental Cell Research, 1997
- Tyrosine Kinase Inhibitors. 12. Synthesis and Structure−Activity Relationships for 6-Substituted 4-(Phenylamino)pyrimido[5,4-d]pyrimidines Designed as Inhibitors of the Epidermal Growth Factor ReceptorJournal of Medicinal Chemistry, 1997
- Tyrosine Kinase Inhibitors. 8. An Unusually Steep Structure−Activity Relationship for Analogues of 4-(3-Bromoanilino)-6,7-dimethoxyquinazoline (PD 153035), a Potent Inhibitor of the Epidermal Growth Factor ReceptorJournal of Medicinal Chemistry, 1996
- Recombinant fibroblast growth factor-1 promotes intimal hyperplasia and angiogenesis in arteries in vivoNature, 1993
- Anti-AngiogenesisAnnals of Surgery, 1972
- Synthetic Antimalarials. The Preparation of Certain 4-Aminoquinolines1Journal of the American Chemical Society, 1946