Design, synthesis, and evaluation of 5-methyl-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine derivatives: novel VEGFR2 kinase inhibitors binding to inactive kinase conformation

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

doi:10.1016/j.bmc.2010.08.017

Design, synthesis, and evaluation of 5-methyl-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine derivatives: novel VEGFR2 kinase inhibitors binding to inactive kinase conformation

Bioorg Med Chem. 2010 Oct 15;18(20):7260-73. doi: 10.1016/j.bmc.2010.08.017. Epub 2010 Aug 13.

Authors

Yuya Oguro¹, Naoki Miyamoto, Kengo Okada, Terufumi Takagi, Hidehisa Iwata, 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. Ooguro_Yuuya@takeda.co.jp

PMID: 20833055
DOI: 10.1016/j.bmc.2010.08.017

Abstract

We synthesized a series of pyrrolo[3,2-d]pyrimidine derivatives and evaluated their application as type-II inhibitors of vascular endothelial growth factor receptor 2 (VEGFR2) kinase. Incorporation of a diphenylurea moiety at the C4-position of the pyrrolo[3,2-d]pyrimidine core via an oxygen linker resulted in compounds that were potent inhibitors of VEGFR2 kinase. Of these derivatives, compound 20d showed the strongest inhibition of VEGF-stimulated proliferation of human umbilical vein endothelial cells (HUVEC). The co-crystal structure of 20d and VEGFR2 revealed that 20d binds to the inactive form of VEGFR2. Further studies indicated that 20d inhibited VEGFR2 kinase with slow dissociation kinetics and also inhibited PDGFR and Tie-2 kinases. Oral administration of the hydrochloride salt of 20d at 3mg/kg/day showed potent inhibition of tumor growth in a DU145 human prostate cancer cell xenograft nude mouse model.

MeSH terms

Administration, Oral
Animals
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / chemistry
Antineoplastic Agents / toxicity
Binding Sites
Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis*
Bridged Bicyclo Compounds, Heterocyclic / chemistry
Bridged Bicyclo Compounds, Heterocyclic / pharmacology
Cells, Cultured
Crystallography, X-Ray
Drug Design
Humans
Mice
Mice, Nude
Phenylurea Compounds / chemical synthesis*
Phenylurea Compounds / chemistry
Phenylurea Compounds / pharmacology
Protein Binding
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / toxicity
Protein Structure, Tertiary
Pyrimidines / chemical synthesis
Pyrimidines / chemistry*
Pyrimidines / toxicity
Pyrroles / chemical synthesis
Pyrroles / chemistry*
Pyrroles / toxicity
Receptor, TIE-2 / antagonists & inhibitors
Receptor, TIE-2 / metabolism
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
Vascular Endothelial Growth Factor Receptor-2 / metabolism
Xenograft Model Antitumor Assays

Substances

1-(2-fluoro-4-((5-methyl-5H-pyrrolo(3,2-d)pyrimidin-4-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea
Antineoplastic Agents
Bridged Bicyclo Compounds, Heterocyclic
Phenylurea Compounds
Protein Kinase Inhibitors
Pyrimidines
Pyrroles
pyrrolopyrimidine
Receptor, TIE-2
Vascular Endothelial Growth Factor Receptor-2