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
  • 1. Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6100, USA. [email protected]
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.