Neutral 5-substituted 4-anilinoquinazolines as potent, orally active inhibitors of erbB2 receptor tyrosine kinase.
Neutral 5-substituted 4-anilinoquinazolines addressed high in vivo clearance and phospholipidosis associated with previous basic compounds. A representative compound 8a inhibited tumor growth in a mouse xenograft model when co-administered with the cytochrome P450 inhibitor 1-aminobenzotriazole (ABT), and data are consistent with pharmacology primarily reflecting inhibition of erbB2 receptor tyrosine kinase.
Ballard
Peter
P
Cancer and Infection Research, AstraZeneca, Mereside, Alderley Park, Macclesfield, UK.
Barlaam
Bernard C
BC
Bradbury
Robert H
RH
Dishington
Allan
A
Hennequin
Laurent F A
LF
Hickinson
D Mark
DM
Hollingsworth
Ian M
IM
Kettle
Jason G
JG
Klinowska
Teresa
T
Ogilvie
Donald J
DJ
Pearson
Stuart E
SE
Scott
James S
JS
Suleman
Abid
A
Whittaker
Robin
R
Williams
Emma J
EJ
Wood
Robin
R
Wright
Lindsay
L
D000284:Administration, Oral; D000814:Aniline Compounds / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols; D049109:Cell Proliferation / Q000187:drug effects; D004285:Dogs; D004357:Drug Synergism; D051379:Mice; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy*; D011799:Quinazolines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D014230:Triazoles / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D000814:Aniline Compounds; D000970:Antineoplastic Agents; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D014230:Triazoles; C033020:1-aminobenzotriazole; C023650:aniline