title: N-phenyl-N'-[4-(5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)phenyl]ureas as novel inhibitors of VEGFR and FGFR kinases.
abstract: 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.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd, 10, Wadai, Tsukuba, Ibaraki 300-4293, Japan. Ooguro_Yuuya@takeda.co.jp
authors.forename: Yuya
authors.initials: Y
authors.lastname: Oguro
authors.forename: Naoki
authors.initials: N
authors.lastname: Miyamoto
authors.forename: Terufumi
authors.initials: T
authors.lastname: Takagi
authors.forename: Kengo
authors.initials: K
authors.lastname: Okada
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Awazu
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miki
authors.forename: Akira
authors.initials: A
authors.lastname: Hori
authors.forename: Keiji
authors.initials: K
authors.lastname: Kamiyama
authors.forename: Shinichi
authors.initials: S
authors.lastname: Imamura
mesh_terms: D001665:Binding Sites; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002478:Cells, Cultured; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D010671:Phenylurea Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: C555238:1-(2-chloro-4-((5-methyl-5H-pyrrolo(3,2-d)pyrimidin-4-yl)oxy)phenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea; D019086:Bridged Bicyclo Compounds, Heterocyclic; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D017468:Receptors, Fibroblast Growth Factor; C527741:pyrrolopyrimidine; D014508:Urea; D042787:Receptor, TIE-2; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor