N-Phenyl- N′-[4-(5 H-pyrrolo[3,2- d]pyrimidin-4-yloxy)phenyl]ureas as novel inhibitors of VEGFR and FGFR kinases

• Published in: Bioorganic & medicinal chemistry 2010-10, Vol.18 (20), p.7150-7163
• Main Authors: Oguro, Yuya, Miyamoto, Naoki, Takagi, Terufumi, Okada, Kengo, Awazu, Yoshiko, Miki, Hiroshi, Hori, Akira, Kamiyama, Keiji, Imamura, Shinichi
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Binding Sites; Biological and medical sciences; Bridged Bicyclo Compounds, Heterocyclic - chemical synthesis; Bridged Bicyclo Compounds, Heterocyclic - chemistry; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Cells, Cultured; Computer Simulation; Crystallography, X-Ray; Drug Design; FGFR; General aspects; Humans; Medical sciences; Pharmacology. Drug treatments; Phenylurea Compounds - chemical synthesis; Phenylurea Compounds - chemistry; Phenylurea Compounds - pharmacology; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Pyrroles - chemical synthesis; Pyrroles - chemistry; Pyrroles - pharmacology; Pyrrolo[3,2- d]pyrimidine; Receptor, TIE-2 - antagonists & inhibitors; Receptor, TIE-2 - metabolism; Receptors, Fibroblast Growth Factor - antagonists & inhibitors; Receptors, Fibroblast Growth Factor - metabolism; Receptors, Platelet-Derived Growth Factor - antagonists & inhibitors; Receptors, Platelet-Derived Growth Factor - metabolism; Receptors, Vascular Endothelial Growth Factor - antagonists & inhibitors; Receptors, Vascular Endothelial Growth Factor - metabolism; Structure-Activity Relationship; Urea; Urea - analogs & derivatives; Urea - chemical synthesis; Urea - pharmacology; VEGFR
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2010.08.042

We have recently reported the discovery of pyrrolo[3,2- d]pyrimidine derivatives 1a and 1b as potent triple inhibitors of vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and Tie-2 kinases. To identify compounds having strong inhibitory activity against fibroblast growth factor receptor (FGFR) kinase, further modification was conducted using the co-crystal structure analysis of VEGFR2 and 1b. Among the compounds synthesized, urea derivative 11l having a piperazine moiety on the terminal benzene ring showed strong inhibitory activity against FGFR1 kinase as well as VEGFR2 kinase. A binding model of 11l complexed with VEGFR2 suggested that the piperazine moiety forms additional interactions with Ile1025 and His1026.