Neutral 5-substituted 4-indazolylaminoquinazolines as potent, orally active inhibitors of erbB2 receptor tyrosine kinase.
We have identified a new series of C-5 substituted indazolylaminoquinazolines as potent erbB2 kinase inhibitors. The lead compound 22 showed excellent in vitro potency, good physical properties, acceptable oral pharmacokinetics in rat and dog, and low human in vitro clearance. It showed at least equivalent activity dose for dose compared to lapatinib in various erbB2- or EGFR-driven xenograft models after chronic oral administration.
Barlaam
Bernard
B
AstraZeneca, Centre de Recherches, Z.I.S.E. La Pompelle, B.P. 1050, 51689 Reims Cedex 2, France. bernard.barlaam2@astrazeneca.com
Acton
David G
DG
Ballard
Peter
P
Bradbury
Robert H
RH
Cross
Darren
D
Ducray
Richard
R
Germain
Hervé
H
Hudson
Kevin
K
Klinowska
Teresa
T
Magnien
Françoise
F
Ogilvie
Donald J
DJ
Olivier
Annie
A
Ross
Helen S
HS
Smith
Robin
R
Trigwell
Cath B
CB
Vautier
Michel
M
Wright
Lindsay
L
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004285:Dogs; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D051638:Ether-A-Go-Go Potassium Channels; D005260:Female; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000077341:Lapatinib; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D008861:Microsomes / Q000187:drug effects; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D011799:Quinazolines / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D015996:Survival Rate; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D051638:Ether-A-Go-Go Potassium Channels; D007191:Indazoles; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C496884:KCNH1 protein, human