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-Sr

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• 作者：Laurent F. Hennequin ; Jack Allen ; Jason Breed ; Jon Curwen ; Michael Fennell ; Tim P. Green ; Christine Lambert-van der Brempt ; Ré ; my Morgentin ; Richard A. Norman ; Annie Olivier ; Ludovic Otterbein
• 刊名：Journal of Medicinal Chemistry
• 出版年：2006
• 出版时间：November 2, 2006
• 年：2006
• 卷：49
• 期：22
• 页码：6465 - 6488
• 全文大小：628K
• 年卷期：v.49,no.22(November 2, 2006)
• ISSN：1520-4804

文摘

Src family kinases (SFKs) are nonreceptor tyrosine kinases that are reported to be critical for cancerprogression. We report here a novel subseries of C-5-substituted anilinoquinazolines that display high affinityand specificity for the tyrosine kinase domain of the c-Src and Abl enzymes. These compounds exhibit highselectivity for SFKs over a panel of recombinant protein kinases, excellent pharmacokinetics, and in vivoactivity 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 lownanomolar concentrations and is highly selective over a range of kinases. AZD0530 displays excellentpharmacokinetic parameters in animal preclinically and in man (t_1/2 = 40 h). AZD0530 is a potent inhibitorof tumor growth in a c-Src-transfected 3T3-fibroblast xenograft model in vivo and led to a significant increasein survival in a highly aggressive, orthotopic model of human pancreatic cancer when dosed orally oncedaily. AZD0530 is currently undergoing clinical evaluation in man.