New heterocyclic analogues of 4-(2-chloro-5-methoxyanilino)quinazolines as potent and selective c-Src kinase inhibitors.
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.
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
Fennell
Mike
M
Germain
Hervé
H
Green
Tim
T
Hennequin
Laurent
L
Morgentin
Rémy
R
Olivier
Annie
A
Plé
Patrick
P
Vautier
Michel
M
Costello
Gerard
G
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
D000814:Aniline Compounds; D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D011799:Quinazolines; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases