Discovery of (+)-N-(3-Aminopropyl)-N-[1-(5-benzyl-3-metlyl-4-oxo-[1,2]thiazolo[5,4-d]pyrimidin-6-yl)-2-metlylpropyl]-4-methylbenzamide (AZD4877), a Kinesin Spindle Protein Inhibitor and Potential Anticancer Agent

被引：40

作者：

Theoclitou, Maria-Elena ^{[1
]}

Aquila, Brian ^{[2
]}

Block, Michael H. ^{[2
]}

Brassil, Patrick J. ^{[2
]}

Castriotta, Lillian ^{[2
]}

Code, Erin ^{[2
]}

Collins, Michael P. ^{[2
]}

Davies, Audrey M. ^{[2
]}

Deegan, Tracy ^{[2
]}

Ezhuthachan, Jayachandran ^{[2
,3
]}

Filla, Sandra ^{[2
,3
]}

Freed, Ellen ^{[2
,3
]}

Hu, Haiqing ^{[2
]}

Huszar, Dennis ^{[2
]}

Jayaraman, Muthusamy

Lawson, Deborah ^{[2
]}

Lewis, Paula M. ^{[2
]}

Nadella, Murali V. P. ^{[2
]}

Oza, Vibha ^{[2
]}

Padmanilayam, Maniyan ^{[4
]}

Pontz, Timothy ^{[2
]}

Ronco, Lucienne ^{[2
,3
]}

Russell, Daniel ^{[2
]}

Whitston, David ^{[2
]}

Zheng, Xiaolan ^{[2
]}

机构：

[1] AstraZeneca, Canc & Infect Res Area, Macclesfield SK10 4TG, Cheshire, England

[2] AstraZeneca R&D Boston, Canc & Infect Res Area, Waltham, MA 02451 USA

[3] AstraZeneca Boston, Boston, MA USA

[4] Organix Inc, Woburn, MA 01801 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2011年 / 54卷 / 19期

关键词：

MITOTIC MOTOR PROTEIN; ANTIMITOTIC DRUG; EG5; MICROTUBULES; MECHANISMS; RESISTANCE; CANCER; TAXOL; KSP; BIPOLARITY;

D O I：

10.1021/jm200629m

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Structure activity relationship analysis identified (+)-N-(3-aminopropyl)-N-[1-(5-benzyl-3-methyl-4-oxo-[1,2]thiazolo[5,4-d]pyrimidin-6-yl)-2-methylpropyl]-4-methylbenzamide (AZD4877), from a series of novel kinesin spindle protein (KSP) inhibitors, as exhibiting both excellent biochemical potency and pharmaceutical properties suitable for clinical development. The selected compound arrested cells in mitosis leading to the formation of the monopolar spindle phenotype characteristic of KSP inhibition and induction of cellular death. A favorable pharmacokinetic profile and notable in vivo efficacy supported the selection of this compound as a clinical candidate for the treatment of cancer.

引用

页码：6734 / 6750

页数：17

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