The discovery of AZD5597, a potent imidazole pyrimidine amide CDK inhibitor suitable for intravenous dosing

被引：36

作者：

Jones, Clifford D. ^{[1
]}

Andrews, David M. ^{[1
]}

Barker, Andrew J. ^{[1
]}

Blades, Kevin ^{[1
]}

Daunt, Paula ^{[1
]}

East, Simon ^{[1
]}

Geh, Catherine ^{[1
]}

Graham, Mark A. ^{[1
]}

Johnson, Keith M. ^{[1
]}

Loddick, Sarah A. ^{[1
]}

McFarland, Heather M. ^{[1
]}

McGregor, Alexandra ^{[1
]}

Moss, Louise ^{[1
]}

Rudge, David A. ^{[1
]}

Simpson, Peter B. ^{[1
]}

Swain, Michael L. ^{[1
]}

Tam, Kin Y. ^{[1
]}

Tucker, Julie A. ^{[2
]}

Walker, Mike ^{[1
]}

机构：

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

[2] AstraZeneca, Lead Generat Discovery Enabling Capabil & Sci, Macclesfield SK10 4TG, Cheshire, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 24期

关键词：

Kinase; Cyclin-dependent kinase; Kinase inhibitor; Imidazole amide; CDK; Cell cycle; Anti-cancer;

D O I：

10.1016/j.bmcl.2008.10.102

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The development of a novel series of imidazole pyrimidine amides as cyclin-dependent kinase (CDK) inhibitors is described. Optimisation of inhibitory potency against multiple CDK's (1, 2 and 9) resulted in imidazole pyrimidine amides with potent in vitro anti-proliferative effects against a range of cancer cell lines. Excellent physiochemical properties and large margins against inhibition of CYP isoforms and the hERG ion channel were achieved by modi. cation of lipophilicity and amine basicity. A candidate with disease model activity in human cancer cell line xenografts and with suitable physiochemical and pharmacokinetic profiles for intravenous (iv) dosing was selected for further development as AZD5597. (C) 2008 Elsevier Ltd. All rights reserved.

引用

页码：6963 / 6967

页数：5

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