Discovery of N-(4-(3-amino-1H-indazol-4-yl)phenyl)-N'-(2-fluoro-5-methylphenyl)urea (ABT-869), a 3-aminoindazole-based orally active multitargeted receptor tyrosine kinase inhibitor.
In our continued efforts to search for potent and novel receptor tyrosine kinase (RTK) inhibitors as potential anticancer agents, we discovered, through a structure-based design, that 3-aminoindazole could serve as an efficient hinge-binding template for kinase inhibitors. By incorporating an N,N'-diaryl urea moiety at the C4-position of 3-aminodazole, a series of RTK inhibitors were generated, which potently inhibited the tyrosine kinase activity of the vascular endothelial growth factor receptor and the platelet-derived growth factor receptor families. A number of compounds with potent oral activity were identified by utilizing an estradiol-induced mouse uterine edema model and an HT1080 human fibrosarcoma xenograft tumor model. In particular, compound 17p (ABT-869) was found to possess favorable pharmacokinetic profiles across different species and display significant tumor growth inhibition in multiple preclinical animal models.
Dai
Yujia
Y
Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6100, USA. yujia.dai@abbott.com
Hartandi
Kresna
K
Ji
Zhiqin
Z
Ahmed
Asma A
AA
Albert
Daniel H
DH
Bauch
Joy L
JL
Bouska
Jennifer J
JJ
Bousquet
Peter F
PF
Cunha
George A
GA
Glaser
Keith B
KB
Harris
Christopher M
CM
Hickman
Dean
D
Guo
Jun
J
Li
Junling
J
Marcotte
Patrick A
PA
Marsh
Kennan C
KC
Moskey
Maria D
MD
Martin
Ruth L
RL
Olson
Amanda M
AM
Osterling
Donald J
DJ
Pease
Lori J
LJ
Soni
Niru B
NB
Stewart
Kent D
KD
Stoll
Vincent S
VS
Tapang
Paul
P
Reuter
David R
DR
Davidsen
Steven K
SK
Michaelides
Michael R
MR
D000255:Adenosine Triphosphate / Q000737:chemistry; D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D004487:Edema / Q000139:chemically induced / Q000473:pathology; D004958:Estradiol; D005260:Female; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007191:Indazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D051379:Mice; D008958:Models, Molecular; D041681:NIH 3T3 Cells; D010671:Phenylurea Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010766:Phosphorylation; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D014599:Uterus / Q000187:drug effects / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D007191:Indazoles; D010671:Phenylurea Compounds; D004958:Estradiol; D000255:Adenosine Triphosphate; C513486:linifanib; D020794:Receptor Protein-Tyrosine Kinases