Discovery of 4-Amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (AZD5363), an Orally Bioavailable, Potent Inhibitor of Akt Kinases

被引：160

作者：

Addie, Matt ^{[1
]}

Ballard, Peter ^{[1
]}

Buttar, David ^{[1
]}

Crafter, Claire ^{[1
]}

Currie, Gordon ^{[1
]}

Davies, Barry R. ^{[1
]}

Debreczeni, Judit ^{[1
]}

Dry, Hannah ^{[1
]}

Dudley, Philippa ^{[1
]}

Greenwood, Ryan ^{[1
]}

Johnson, Paul D. ^{[1
]}

Kettle, Jason G. ^{[1
]}

Lane, Clare ^{[1
]}

Lamont, Gillian ^{[1
]}

Leach, Andrew ^{[1
]}

Luke, Richard W. A. ^{[1
]}

Morris, Jeff ^{[1
]}

Ogilvie, Donald ^{[1
]}

Page, Ken ^{[1
]}

Pass, Martin ^{[1
]}

Pearson, Stuart ^{[1
]}

Ruston, Linette ^{[1
]}

机构：

[1] AstraZeneca, Oncol iMed, Macclesfield SK10 4TG, Cheshire, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2013年 / 56卷 / 05期

关键词：

PRECLINICAL PHARMACOLOGY; IDENTIFICATION; AKT/PKB; DESIGN;

D O I：

10.1021/jm301762v

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Wide-ranging exploration of analogues of an ATP-competitive pyrrolopyrimidine inhibitor of Akt led to the discovery of clinical candidate AZD5363, which showed increased potency, reduced hERG affinity, and higher selectivity against the closely related AGC kinase ROCK. This compound demonstrated good preclinical drug metabolism and pharmacokinetics (DMPK) properties and, after oral dosing, showed pharmacodynamic knockdown of phosphorylation of Akt and downstream biomarkers in vivo, and inhibition of tumor growth in a breast cancer xenograft model.

引用

页码：2059 / 2073

页数：15

共 18 条

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