Synthesis and structure-activity relationship of 6-arylureido-3-pyrrol-2-ylmethylideneindolin-2-one derivatives as potent receptor tyrosine kinase inhibitors.
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.
Khanwelkar
Rahul R
RR
School of Pharmacy, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
Chen
Grace Shiahuy
GS
Wang
Hsiao-Chun
HC
Yu
Chao-Wu
CW
Huang
Chiung-Hua
CH
Lee
On
O
Chen
Chih-Hung
CH
Hwang
Chrong-Shiong
CS
Ko
Ching-Huai
CH
Chou
Nien-Tzu
NT
Lin
Mai-Wei
MW
Wang
Ling-Mei
LM
Chen
Yen-Chun
YC
Hseu
Tzong-Hsiung
TH
Chang
Chia-Ni
CN
Hsu
Hui-Chun
HC
Lin
Hui-Chi
HC
Shih
Ying-Chu
YC
Chou
Shuen-Hsiang
SH
Tseng
Hsiang-Wen
HW
Liu
Chih-Peng
CP
Tu
Chia-Mu
CM
Hu
Tsan-Lin
TL
Tsai
Yuan-Jang
YJ
Chern
Ji-Wang
JW
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
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