title: Synthesis and structure-activity relationship of 6-arylureido-3-pyrrol-2-ylmethylideneindolin-2-one derivatives as potent receptor tyrosine kinase inhibitors.
abstract: A series of new ureidoindolin-2-one derivatives were synthesized and evaluated as inhibitors of receptor tyrosine kinases. Investigation of structure-activity relationships at positions 5, 6, and 7 of the oxindole skeleton led to the identification of 6-ureido-substituted 3-pyrrolemethylidene-2-oxindole derivatives that potently inhibited both the vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) families of receptor tyrosine kinases. Several derivatives showed potency against the PDGFR inhibiting both its enzymatic and cellular functions in the single-digit nanomolar range. Among them, compound 35 was a potent inhibitor against tyrosine kinases, including VEGFR and PDGFR families, as well as Aurora kinases. Inhibitor 36 (non-substituted on the pyrrole or phenyl ring) had a moderate pharmacokinetic profile and completely inhibited tumor growth initiated with the myeloid leukemia cell line, MV4-11, in a subcutaneous xenograft model in BALB/c nude mice.
authors.affiliation: School of Pharmacy, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
authors.forename: Rahul R
authors.initials: RR
authors.lastname: Khanwelkar
authors.forename: Grace Shiahuy
authors.initials: GS
authors.lastname: Chen
authors.forename: Hsiao-Chun
authors.initials: HC
authors.lastname: Wang
authors.forename: Chao-Wu
authors.initials: CW
authors.lastname: Yu
authors.forename: Chiung-Hua
authors.initials: CH
authors.lastname: Huang
authors.forename: On
authors.initials: O
authors.lastname: Lee
authors.forename: Chih-Hung
authors.initials: CH
authors.lastname: Chen
authors.forename: Chrong-Shiong
authors.initials: CS
authors.lastname: Hwang
authors.forename: Ching-Huai
authors.initials: CH
authors.lastname: Ko
authors.forename: Nien-Tzu
authors.initials: NT
authors.lastname: Chou
authors.forename: Mai-Wei
authors.initials: MW
authors.lastname: Lin
authors.forename: Ling-Mei
authors.initials: LM
authors.lastname: Wang
authors.forename: Yen-Chun
authors.initials: YC
authors.lastname: Chen
authors.forename: Tzong-Hsiung
authors.initials: TH
authors.lastname: Hseu
authors.forename: Chia-Ni
authors.initials: CN
authors.lastname: Chang
authors.forename: Hui-Chun
authors.initials: HC
authors.lastname: Hsu
authors.forename: Hui-Chi
authors.initials: HC
authors.lastname: Lin
authors.forename: Ying-Chu
authors.initials: YC
authors.lastname: Shih
authors.forename: Shuen-Hsiang
authors.initials: SH
authors.lastname: Chou
authors.forename: Hsiang-Wen
authors.initials: HW
authors.lastname: Tseng
authors.forename: Chih-Peng
authors.initials: CP
authors.lastname: Liu
authors.forename: Chia-Mu
authors.initials: CM
authors.lastname: Tu
authors.forename: Tsan-Lin
authors.initials: TL
authors.lastname: Hu
authors.forename: Yuan-Jang
authors.initials: YJ
authors.lastname: Tsai
authors.forename: Ji-Wang
authors.initials: JW
authors.lastname: Chern
mesh_terms: D000818:Animals; D064127:Aurora Kinases; D001665:Binding Sites; D045744:Cell Line, Tumor; D003198:Computer Simulation; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D007951:Leukemia, Myeloid / Q000188:drug therapy; D051379:Mice; D000078183:Oxindoles; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000627:therapeutic use / Q000633:toxicity; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011758:Pyrroles / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity
chemical_list: C559235:(Z)-1-(2-oxo-3-(1H-pyrrol-2-ylmethylene)-2,3-dihydro-1H-indol-6-yl)-3-phenyl-urea; C559234:(Z)-5-(6-(3-(4-methoxyphenyl)-ureido)-2-oxo-1,2-dihydroindol-3-ylidene-methyl)-4-methyl-1H-pyrrole-3-carboxylic acid; D007211:Indoles; D000078183:Oxindoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; C456900:indolin-2-one; C022960:2-oxindole; D014508:Urea; D066246:ErbB Receptors; D017479:Receptors, Platelet-Derived Growth Factor; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases