Discovery of Novel 3-Quinoline Carboxamides as Potent, Selective, and Orally Bioavailable Inhibitors of Ataxia Telangiectasia Mutated (ATM) Kinase

被引：61

作者：

Degorce, Sebastien L. ^{[1
,2
]}

Barlaam, Bernard ^{[1
]}

Cadogan, Elaine ^{[1
]}

Dishington, Allan ^{[1
]}

Ducray, Richard ^{[2
]}

Glossop, Steven C. ^{[1
]}

Hassall, Lorraine A. ^{[1
]}

Lach, Franck ^{[2
]}

Lau, Alan ^{[1
]}

McGuire, Thomas M. ^{[1
]}

Nowak, Thorsten ^{[1
]}

Ouvry, Gilles ^{[2
]}

Pike, Kurt G. ^{[1
]}

Thomason, Andrew G. ^{[1
]}

机构：

[1] AstraZeneca, Oncol Innovat Med Unit, Alderley Pk, Macclesfield SK10 4TG, Cheshire, England

[2] AstraZeneca, Ctr Rech, Oncol Innovat Med Unit, BP 1050, F-51689 Reims 2, France

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2016年 / 59卷 / 13期

关键词：

PROTEIN-KINASE; IN-VIVO; ACTIVATION; RADIATION; DESIGN; REPAIR;

D O I：

10.1021/acs.jmedchem.6b00519

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A novel series of 3-quinoline carboxamides has been discovered and optimized as selective inhibitors of the ataxia telangiectasia mutated (ATM) kinase. From a modestly potent HTS hit (4), we identified molecules such as 6-[6-(methoxymethyl)-3-pyridinyl]-4-{[(1R)-1-(tetrahydro-2H-pyran-4-yl)ethyl]amino}-3-quinolinecarboxamide (72) and 7-fluoro-6-[6-(methoxymethyl)pyridin-3-yl]-4-{[(1S)-1-(1-methyl-1H-pyrazol-3-yl)ethyl]amino}quinoline-3-carboxamide (74) as potent and highly selective ATM inhibitors with overall ADME properties suitable for oral administration. 72 and 74 constitute excellent oral tools to probe ATM inhibition in vivo. Efficacy in combination with the DSB-inducing agent irinotecan was observed in a disease relevant model.

引用

页码：6281 / 6292

页数：12

共 50 条

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