title: 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.
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.
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: Kengo
authors.initials: K
authors.lastname: Okada
authors.forename: Terufumi
authors.initials: T
authors.lastname: Takagi
authors.forename: Hidehisa
authors.initials: H
authors.lastname: Iwata
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: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D001665:Binding Sites; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010671:Phenylurea Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C555239:1-(2-fluoro-4-((5-methyl-5H-pyrrolo(3,2-d)pyrimidin-4-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea; D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C527741:pyrrolopyrimidine; D042787:Receptor, TIE-2; D040301:Vascular Endothelial Growth Factor Receptor-2