2. Academic Validation
  3. Thienopyrimidine ureas as novel and potent multitargeted receptor tyrosine kinase inhibitors

Thienopyrimidine ureas as novel and potent multitargeted receptor tyrosine kinase inhibitors

  • J Med Chem. 2005 Sep 22;48(19):6066-83. doi: 10.1021/jm050458h.
Yujia Dai 1,  Yan Guo,  Robin R Frey,  Zhiqin Ji,  Michael L Curtin,  Asma A Ahmed,  Daniel H Albert,  Lee Arnold,  Shannon S Arries,  Teresa Barlozzari,  Joy L Bauch,  Jennifer J Bouska,  Peter F Bousquet,  George A Cunha,  Keith B Glaser,  Jun Guo,  Junling Li,  Patrick A Marcotte,  Kennan C Marsh,  Maria D Moskey,  Lori J Pease,  Kent D Stewart,  Vincent S Stoll,  Paul Tapang,  Neil Wishart,  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. yuija.dai@abbott.com
PMID: 16162008 DOI: 10.1021/jm050458h
Abstract

A series of novel thienopyrimidine-based receptor tyrosine kinase inhibitors has been discovered. Investigation of structure-activity relationships at the 5- and 6-positions of the thienopyrimidine nucleus led to a series of N,N'-diaryl ureas that potently inhibit all of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) Receptor Tyrosine Kinases. A kinase insert domain-containing receptor (VEGFR2/KDR/Flk-1) homology model suggests that these compounds bind to the "inactive conformation" of the Enzyme with the urea portion extending into the back hydrophobic pocket adjacent to the adenosine 5'-triphosphate (ATP) binding site. A number of compounds have been identified as displaying excellent in vivo potency. In particular, compounds 28 and 76 possess favorable pharmacokinetic (PK) profiles and demonstrate potent antitumor efficacy against the HT1080 human fibrosarcoma xenograft tumor growth model (tumor growth inhibition (TGI) = 75% at 25 mg/kg.day, per os (po)).

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