Thienopyrimidine ureas as novel and potent multitargeted receptor tyrosine kinase inhibitors.
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)).
Dai
Yujia
Y
Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6100, USA. yuija.dai@abbott.com
Guo
Yan
Y
Frey
Robin R
RR
Ji
Zhiqin
Z
Curtin
Michael L
ML
Ahmed
Asma A
AA
Albert
Daniel H
DH
Arnold
Lee
L
Arries
Shannon S
SS
Barlozzari
Teresa
T
Bauch
Joy L
JL
Bouska
Jennifer J
JJ
Bousquet
Peter F
PF
Cunha
George A
GA
Glaser
Keith B
KB
Guo
Jun
J
Li
Junling
J
Marcotte
Patrick A
PA
Marsh
Kennan C
KC
Moskey
Maria D
MD
Pease
Lori J
LJ
Stewart
Kent D
KD
Stoll
Vincent S
VS
Tapang
Paul
P
Wishart
Neil
N
Davidsen
Steven K
SK
Michaelides
Michael R
MR
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
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