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

Yuya Oguro; Naoki Miyamoto; Terufumi Takagi; Kengo Okada; Yoshiko Awazu; Hiroshi Miki; Akira Hori; Keiji Kamiyama; Shinichi Imamura

doi:10.1016/j.bmc.2010.08.042

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

Bioorg Med Chem. 2010 Oct 15;18(20):7150-63. doi: 10.1016/j.bmc.2010.08.042. Epub 2010 Aug 25.

Authors

Yuya Oguro¹, Naoki Miyamoto, Terufumi Takagi, Kengo Okada, Yoshiko Awazu, Hiroshi Miki, Akira Hori, Keiji Kamiyama, Shinichi Imamura

Affiliation

¹ Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd, 10, Wadai, Tsukuba, Ibaraki 300-4293, Japan. [email protected]

PMID: 20833551
DOI: 10.1016/j.bmc.2010.08.042

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.

MeSH terms

Binding Sites
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
Humans
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
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 / analogs & derivatives*
Urea / chemical synthesis
Urea / pharmacology

Substances

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
Bridged Bicyclo Compounds, Heterocyclic
Phenylurea Compounds
Protein Kinase Inhibitors
Pyrimidines
Pyrroles
Receptors, Fibroblast Growth Factor
pyrrolopyrimidine
Urea
Receptor, TIE-2
Receptors, Platelet-Derived Growth Factor
Receptors, Vascular Endothelial Growth Factor