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Thienopyrimidine Ureas as Novel and Potent Multitargeted Receptor Tyrosine Kinase Inhibitors
- Source :
- Journal of Medicinal Chemistry; September 2005, Vol. 48 Issue: 19 p6066-6083, 18p
- Publication Year :
- 2005
-
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 (KDR) 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 <BO>28</BO> and <BO>76</BO> 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)).
Details
- Language :
- English
- ISSN :
- 00222623 and 15204804
- Volume :
- 48
- Issue :
- 19
- Database :
- Supplemental Index
- Journal :
- Journal of Medicinal Chemistry
- Publication Type :
- Periodical
- Accession number :
- ejs7748877