title: 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.
abstract: 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.
authors.affiliation: Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6100, USA. yujia.dai@abbott.com
authors.forename: Yujia
authors.initials: Y
authors.lastname: Dai
authors.forename: Kresna
authors.initials: K
authors.lastname: Hartandi
authors.forename: Zhiqin
authors.initials: Z
authors.lastname: Ji
authors.forename: Asma A
authors.initials: AA
authors.lastname: Ahmed
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Albert
authors.forename: Joy L
authors.initials: JL
authors.lastname: Bauch
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Bouska
authors.forename: Peter F
authors.initials: PF
authors.lastname: Bousquet
authors.forename: George A
authors.initials: GA
authors.lastname: Cunha
authors.forename: Keith B
authors.initials: KB
authors.lastname: Glaser
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Harris
authors.forename: Dean
authors.initials: D
authors.lastname: Hickman
authors.forename: Jun
authors.initials: J
authors.lastname: Guo
authors.forename: Junling
authors.initials: J
authors.lastname: Li
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Marcotte
authors.forename: Kennan C
authors.initials: KC
authors.lastname: Marsh
authors.forename: Maria D
authors.initials: MD
authors.lastname: Moskey
authors.forename: Ruth L
authors.initials: RL
authors.lastname: Martin
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Olson
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Osterling
authors.forename: Lori J
authors.initials: LJ
authors.lastname: Pease
authors.forename: Niru B
authors.initials: NB
authors.lastname: Soni
authors.forename: Kent D
authors.initials: KD
authors.lastname: Stewart
authors.forename: Vincent S
authors.initials: VS
authors.lastname: Stoll
authors.forename: Paul
authors.initials: P
authors.lastname: Tapang
authors.forename: David R
authors.initials: DR
authors.lastname: Reuter
authors.forename: Steven K
authors.initials: SK
authors.lastname: Davidsen
authors.forename: Michael R
authors.initials: MR
authors.lastname: Michaelides
mesh_terms: 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
chemical_list: D020533:Angiogenesis Inhibitors; D007191:Indazoles; D010671:Phenylurea Compounds; D004958:Estradiol; D000255:Adenosine Triphosphate; C513486:linifanib; D020794:Receptor Protein-Tyrosine Kinases