title: Optimization and SAR for dual ErbB-1/ErbB-2 tyrosine kinase inhibition in the 6-furanylquinazoline series.
abstract: Synthetic modifications on a 6-furanylquinazoline scaffold to optimize the dual ErbB-1/ErbB-2 tyrosine kinase inhibition afforded consistent SAR whereby a 4-(3-fluorobenzyloxy)-3-haloanilino provided the best enzyme potency and cellular selectivity. Changes made to the 6-furanyl group had little impact on the enzyme activity, but appeared to dramatically affect the cellular efficacy. The discovery of lapatinib emerged from this work.
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: Kimberly G
authors.initials: KG
authors.lastname: Petrov
authors.forename: Yue-Mei
authors.initials: YM
authors.lastname: Zhang
authors.forename: Malcolm
authors.initials: M
authors.lastname: Carter
authors.forename: G Stuart
authors.initials: GS
authors.lastname: Cockerill
authors.forename: Scott
authors.initials: S
authors.lastname: Dickerson
authors.forename: Cassandra A
authors.initials: CA
authors.lastname: Gauthier
authors.forename: Yu
authors.initials: Y
authors.lastname: Guo
authors.forename: Robert A
authors.initials: RA
authors.lastname: Mook
authors.forename: David W
authors.initials: DW
authors.lastname: Rusnak
authors.forename: Ann L
authors.initials: AL
authors.lastname: Walker
authors.forename: Edgar R
authors.initials: ER
authors.lastname: Wood
authors.forename: Karen E
authors.initials: KE
authors.lastname: Lackey
mesh_terms: D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D000077341:Lapatinib; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D066246:ErbB Receptors; D005663:Furans; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases