Novel tricyclic azepine derivatives: Biological evaluation of pyrimido[4,5-b]-1,4-benzoxazepines, thiazepines, and diazepines as inhibitors of the epidermal growth factor receptor tyrosine kinase.
Novel tricyclic derivatives containing an oxazepine, thiazepine, or diazepine ring were studied for their EGFR tyrosine kinase inhibitory activity. While the oxazepines were in general more potent than thiazepines, the diazepines displayed somewhat different structure-activity relationships. Moreover, the diazepines, in contrast to the oxazepines, showed appreciable inhibitory activity against the KDR tyrosine kinase. Furthermore, both oxazepines and diazepines demonstrated significant ability to inhibit autophosphorylation of EGFR in DiFi cells (generally, IC(50) values in the single-digit micromolar to submicromolar range).
Smith
Leon
L
Department of Chemistry, ImClone Systems Incorporated, 710 Parkside Avenue, Suite 2, Brooklyn, NY 11226, USA. leon.smith@bms.com
Wong
Wai C
WC
Kiselyov
Alexander S
AS
Burdzovic-Wizemann
Sabina
S
Mao
Yunyu
Y
Xu
Yongjiang
Y
Duncton
Matthew A J
MA
Kim
Ki
K
Piatnitski
Evgueni L
EL
Doody
Jacqueline F
JF
Wang
Ying
Y
Rosler
Robin L
RL
Milligan
Daniel
D
Columbus
John
J
Balagtas
Chris
C
Lee
Sui Ping
SP
Konovalov
Andrey
A
Hadari
Yaron R
YR
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001381:Azepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D010766:Phosphorylation / Q000187:drug effects; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors
D000970:Antineoplastic Agents; D001381:Azepines; D006575:Heterocyclic Compounds, 3-Ring; D009363:Neoplasm Proteins; D066246:ErbB Receptors; D040301:Vascular Endothelial Growth Factor Receptor-2