Synthesis and structure based optimization of novel Akt inhibitors

被引：80

作者：

Lippa, Blaise ^{[1
]}

Pan, Gonghua ^{[1
]}

Corbett, Matthew ^{[1
]}

Li, Chao ^{[1
]}

Kauffman, Goss S. ^{[1
]}

Pandit, Jayvardhan ^{[1
]}

Robinson, Shaughnessy ^{[1
]}

Wei, Liuqing ^{[1
]}

Kozina, Ekaterina ^{[1
]}

Marr, Eric S. ^{[1
]}

Borzillo, Gary ^{[1
]}

Knauth, Elisabeth ^{[1
]}

Barbacci-Tobin, Elsa G. ^{[1
]}

Vincent, Patrick ^{[1
]}

Troutman, Merin ^{[1
]}

Baker, Deborah ^{[1
]}

Rajamohan, Francis ^{[1
]}

Kakar, Shefali ^{[1
]}

Clark, Tracey ^{[1
]}

Morris, Joel ^{[1
]}

机构：

[1] Pfizer Inc, PGRD Groton, Groton, CT 06340 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 11期

关键词：

Akt; pyrrolopyrimidine; spiroindoline; imidazopiperidine;

D O I：

10.1016/j.bmcl.2008.04.034

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Based on a high throughput screening hit, pyrrolopyrimidine inhibitors of the Akt kinase are explored. X-ray co-crystal structures of two lead series results in the understanding of key binding interactions, the design of new lead series, and enhanced potency. The syntheses of these series and their biological activities are described. Spiroindoline 13j is found to have an Akt1 kinase IC(50) of 2.4 +/- 0.6 nM, Akt cell potency of 50 +/- 19 nM, and provides 68% inhibition of tumor growth in a mouse xenograft model (50 mg/kg, qd, po). (C) 2008 Elsevier Ltd. All rights reserved.

引用

页码：3359 / 3363

页数：5

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