title: Thienopyrimidine ureas as novel and potent multitargeted receptor tyrosine kinase inhibitors.
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)).
authors.affiliation: Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6100, USA. yuija.dai@abbott.com
authors.forename: Yujia
authors.initials: Y
authors.lastname: Dai
authors.forename: Yan
authors.initials: Y
authors.lastname: Guo
authors.forename: Robin R
authors.initials: RR
authors.lastname: Frey
authors.forename: Zhiqin
authors.initials: Z
authors.lastname: Ji
authors.forename: Michael L
authors.initials: ML
authors.lastname: Curtin
authors.forename: Asma A
authors.initials: AA
authors.lastname: Ahmed
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Albert
authors.forename: Lee
authors.initials: L
authors.lastname: Arnold
authors.forename: Shannon S
authors.initials: SS
authors.lastname: Arries
authors.forename: Teresa
authors.initials: T
authors.lastname: Barlozzari
authors.forename: Joy L
authors.initials: JL
authors.lastname: Bauch
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Bouska
authors.forename: Peter F
authors.initials: PF
authors.lastname: Bousquet
authors.forename: George A
authors.initials: GA
authors.lastname: Cunha
authors.forename: Keith B
authors.initials: KB
authors.lastname: Glaser
authors.forename: Jun
authors.initials: J
authors.lastname: Guo
authors.forename: Junling
authors.initials: J
authors.lastname: Li
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Marcotte
authors.forename: Kennan C
authors.initials: KC
authors.lastname: Marsh
authors.forename: Maria D
authors.initials: MD
authors.lastname: Moskey
authors.forename: Lori J
authors.initials: LJ
authors.lastname: Pease
authors.forename: Kent D
authors.initials: KD
authors.lastname: Stewart
authors.forename: Vincent S
authors.initials: VS
authors.lastname: Stoll
authors.forename: Paul
authors.initials: P
authors.lastname: Tapang
authors.forename: Neil
authors.initials: N
authors.lastname: Wishart
authors.forename: Steven K
authors.initials: SK
authors.lastname: Davidsen
authors.forename: Michael R
authors.initials: MR
authors.lastname: Michaelides
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004487:Edema / Q000139:chemically induced / Q000473:pathology; D004958:Estradiol; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D008958:Models, Molecular; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014599:Uterus / Q000187:drug effects / Q000473:pathology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D011743:Pyrimidines; C476003:thienopyrimidine; D004958:Estradiol; D000255:Adenosine Triphosphate; D014508:Urea; D017479:Receptors, Platelet-Derived Growth Factor; D040301:Vascular Endothelial Growth Factor Receptor-2