2. Academic Validation
  3. 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

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

  • J Med Chem. 2007 Apr 5;50(7):1584-97. doi: 10.1021/jm061280h.
Yujia Dai 1,  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
Affiliations

Affiliation

  • 1 Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6100, USA. yujia.dai@abbott.com
PMID: 17343372 DOI: 10.1021/jm061280h
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.

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