title: New heterocyclic analogues of 4-(2-chloro-5-methoxyanilino)quinazolines as potent and selective c-Src kinase inhibitors.
abstract: A series of 5,7-disubstituted quinazolines, bearing 4-heteroaryl substituents such as 2-pyridinylamine or 2-pyrazinylamine, has been synthetised and evaluated as c-Src kinase inhibitors. Highly potent inhibition, high selectivity and physical properties suitable for oral dosing were achieved within this series: 23d and 42 were identified as sub-0.1muM inhibitors in a c-Src-driven cell proliferation assay and displayed adequate rat pharmacokinetics after 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: Mike
authors.initials: M
authors.lastname: Fennell
authors.forename: Hervé
authors.initials: H
authors.lastname: Germain
authors.forename: Tim
authors.initials: T
authors.lastname: Green
authors.forename: Laurent
authors.initials: L
authors.lastname: Hennequin
authors.forename: Rémy
authors.initials: R
authors.lastname: Morgentin
authors.forename: Annie
authors.initials: A
authors.lastname: Olivier
authors.forename: Patrick
authors.initials: P
authors.lastname: Plé
authors.forename: Michel
authors.initials: M
authors.lastname: Vautier
authors.forename: Gerard
authors.initials: G
authors.lastname: Costello
mesh_terms: D000814:Aniline Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D002455:Cell Division; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D007536:Isomerism; D007700:Kinetics; D008958:Models, Molecular; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D019061:src-Family Kinases
chemical_list: D000814:Aniline Compounds; D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D011799:Quinazolines; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases