N-(5-Chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine, a novel, highly selective, orally available, dual-specific c-Src/Abl kinase inhibitor

被引:298
作者
Hennequin, Laurent F.
Allen, Jack
Breed, Jason
Curwen, Jon
Fennell, Michael
Green, Tim P.
Brempt, Christine Lambert-van der
Morgentin, Remy
Norman, Richard A.
Olivier, Annie
Otterbein, Ludovic
Ple, Patrick A.
Warin, Nicolas
Costello, Gerard
机构
[1] AstraZeneca, ZISE La Pompelle, Ctr Rech, F-51689 Reims 2, France
[2] AstraZeneca, Macclesfield SK10 4TG, Cheshire, England
关键词
D O I
10.1021/jm060434q
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Src family kinases (SFKs) are nonreceptor tyrosine kinases that are reported to be critical for cancer progression. We report here a novel subseries of C-5-substituted anilinoquinazolines that display high affinity and specificity for the tyrosine kinase domain of the c-Src and Abl enzymes. These compounds exhibit high selectivity for SFKs over a panel of recombinant protein kinases, excellent pharmacokinetics, and in vivo activity following oral dosing. N-(5-Chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl) ethoxy]-5(tetrahydro-2H-pyran-4-yloxy) quinazolin-4-amine (AZD0530) inhibits c-Src and Abl enzymes at low nanomolar concentrations and is highly selective over a range of kinases. AZD0530 displays excellent pharmacokinetic parameters in animal preclinically and in man (t(1/2) = 40 h). AZD0530 is a potent inhibitor of tumor growth in a c-Src-transfected 3T3-fibroblast xenograft model in vivo and led to a significant increase in survival in a highly aggressive, orthotopic model of human pancreatic cancer when dosed orally once daily. AZD0530 is currently undergoing clinical evaluation in man.
引用
收藏
页码:6465 / 6488
页数:24
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