A new series of neutral 5-substituted 4-anilinoquinazolines as potent, orally active inhibitors of erbB2 receptor tyrosine kinase.
Starting from initial lead 1 containing a basic 5-substituent, optimisation of the glycolamide-derived neutral 5-substituent led to potent inhibitors of erbB2 with good pharmacokinetics. Representative compounds 19 and 21 inhibited phosphorylation of erbB2 in a mouse BT474C xenograft model after oral administration.
AstraZeneca, Centre de Recherches, Z.I.S.E. La Pompelle B.P. 1050, 51689 Reims Cedex 2, France. bernard.barlaam2@astrazeneca.com
Bernard
B
Barlaam
Peter
P
Ballard
Robert H
RH
Bradbury
Richard
R
Ducray
Hervé
H
Germain
D Mark
DM
Hickinson
Kevin
K
Hudson
Jason G
JG
Kettle
Teresa
T
Klinowska
Françoise
F
Magnien
Donald J
DJ
Ogilvie
Annie
A
Olivier
Stuart E
SE
Pearson
James S
JS
Scott
Abid
A
Suleman
Cath B
CB
Trigwell
Michel
M
Vautier
Robin D
RD
Whittaker
Robin
R
Wood
D000284:Administration, Oral; D000818:Animals; D002460:Cell Line; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011799:Quinazolines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases