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: Yujia Dai, Kresna Hartandi, Zhiqin Ji, Asma A Ahmed, Daniel H Albert, Joy L Bauch, Jennifer J Bouska, Peter F Bousquet, George A Cunha, Keith B Glaser, Christopher M Harris, Dean Hickman, Jun Guo, Junling Li, Patrick A Marcotte, Kennan C Marsh, Maria D Moskey, Ruth L Martin, Amanda M Olson, Donald J Osterling, Lori J Pease, Niru B Soni, Kent D Stewart, Vincent S Stoll, Paul Tapang, David R Reuter, Steven K Davidsen, Michael R Michaelides
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 50 Issue 7 Pg. 1584-97 (Apr 05 2007) ISSN: 0022-2623 [Print] United States
• PMID: 17343372 (Publication Type: Journal Article)

Chemical References

• Angiogenesis Inhibitors
• Indazoles
• Phenylurea Compounds
• Estradiol
• Adenosine Triphosphate
• linifanib
• Receptor Protein-Tyrosine Kinases

Topics

• Adenosine Triphosphate (chemistry)
• Administration, Oral
• Angiogenesis Inhibitors (chemical synthesis, chemistry, pharmacology)
• Animals
• Binding Sites
• Edema (chemically induced, pathology)
• Estradiol
• Female
• Humans
• Hydrophobic and Hydrophilic Interactions
• Indazoles (chemical synthesis, chemistry, pharmacology)
• Male
• Mice
• Models, Molecular
• NIH 3T3 Cells
• Phenylurea Compounds (chemical synthesis, chemistry, pharmacology)
• Phosphorylation
• Receptor Protein-Tyrosine Kinases (antagonists & inhibitors, chemistry, metabolism)
• Structure-Activity Relationship
• Uterus (drug effects, pathology)
• Xenograft Model Antitumor Assays