title: Neutral 5-substituted 4-indazolylaminoquinazolines as potent, orally active inhibitors of erbB2 receptor tyrosine kinase.
abstract: 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.
authors.affiliation: AstraZeneca, Centre de Recherches, Z.I.S.E. La Pompelle, B.P. 1050, 51689 Reims Cedex 2, France. bernard.barlaam2@astrazeneca.com
authors.forename: Bernard
authors.initials: B
authors.lastname: Barlaam
authors.forename: David G
authors.initials: DG
authors.lastname: Acton
authors.forename: Peter
authors.initials: P
authors.lastname: Ballard
authors.forename: Robert H
authors.initials: RH
authors.lastname: Bradbury
authors.forename: Darren
authors.initials: D
authors.lastname: Cross
authors.forename: Richard
authors.initials: R
authors.lastname: Ducray
authors.forename: Hervé
authors.initials: H
authors.lastname: Germain
authors.forename: Kevin
authors.initials: K
authors.lastname: Hudson
authors.forename: Teresa
authors.initials: T
authors.lastname: Klinowska
authors.forename: Françoise
authors.initials: F
authors.lastname: Magnien
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Ogilvie
authors.forename: Annie
authors.initials: A
authors.lastname: Olivier
authors.forename: Helen S
authors.initials: HS
authors.lastname: Ross
authors.forename: Robin
authors.initials: R
authors.lastname: Smith
authors.forename: Cath B
authors.initials: CB
authors.lastname: Trigwell
authors.forename: Michel
authors.initials: M
authors.lastname: Vautier
authors.forename: Lindsay
authors.initials: L
authors.lastname: Wright
mesh_terms: 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
chemical_list: 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