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新型3-喹啉甲酰胺作为共济失调毛细血管扩张突变（ATM）激酶的强效、选择性且口服生物可利用抑制剂的发现。

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

作者信息

Degorce Sébastien L, Barlaam Bernard, Cadogan Elaine, Dishington Allan, Ducray Richard, Glossop Steven C, Hassall Lorraine A, Lach Franck, Lau Alan, McGuire Thomas M, Nowak Thorsten, Ouvry Gilles, Pike Kurt G, Thomason Andrew G

机构信息

Oncology Innovative Medicines Unit, AstraZeneca , Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.

Oncology Innovative Medicines Unit, AstraZeneca, Centre de Recherches , Z.I. la Pompelle, BP 1050, 51689 Reims Cedex 2, France.

出版信息

J Med Chem. 2016 Jul 14;59(13):6281-92. doi: 10.1021/acs.jmedchem.6b00519. Epub 2016 Jun 16.

DOI:10.1021/acs.jmedchem.6b00519
PMID:27259031
Abstract

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.

摘要

已发现并优化了一系列新型的3-喹啉甲酰胺，作为共济失调毛细血管扩张突变（ATM）激酶的选择性抑制剂。从一个活性一般的高通量筛选命中化合物（4）开始，我们鉴定出了如6-[6-(甲氧基甲基)-3-吡啶基]-4-{[(1R)-1-(四氢-2H-吡喃-4-基)乙基]氨基}-3-喹啉甲酰胺（72）和7-氟-6-[6-(甲氧基甲基)吡啶-3-基]-4-{[(1S)-1-(1-甲基-1H-吡唑-3-基)乙基]氨基}喹啉-3-甲酰胺（74）等分子，它们是强效且高度选择性的ATM抑制剂，具有适合口服给药的整体药代动力学性质。72和74是用于在体内探究ATM抑制作用的优秀口服工具。在一个疾病相关模型中观察到了与DNA双链断裂诱导剂伊立替康联合使用时的疗效。

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