Thienopyrimidine ureas as novel and potent multitargeted receptor tyrosine kinase inhibitors.

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Dai Y, Guo Y, Frey RR, Ji Z, Curtin ML, Ahmed AA, Albert DH, Arnold L, Arries SS, Barlozzari T, Bauch JL, Bouska JJ, Bousquet PF, Cunha GA, Glaser KB, Guo J, Li J, Marcotte PA, Marsh KC, Moskey MD, Pease LJ, Stewart KD, Stoll VS, Tapang P, Wishart N, Davidsen SK, Michaelides MR

Thienopyrimidine ureas as novel and potent multitargeted receptor tyrosine kinase inhibitors.

J Med Chem. 2005 Sep 22;48(19):6066-83.

PubMed ID

16162008 [ View in PubMed

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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 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)).

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Sunitinib	Vascular endothelial growth factor receptor 2	IC 50 (nM)	18	7.5	22	Details