- Discovery of Novel 3-Quinoline Carboxamides as Potent, Selective, and Orally Bioavailable Inhibitors of Ataxia Telangiectasia Mutated (ATM) Kinase
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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.
- 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.
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supporting information
p. 6281 - 6292
(2016/07/26)
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- Controlled derivatization of polyhalogenated quinolines utilizing selective cross-coupling reactions
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Straightforward procedures for the derivatization of tri- and tetrahalogenated quinolines utilizing sequential selective Pd-catalyzed cross-coupling reactions are described. Taking advantage of intrinsic halide reactivity, substrate control, and appropria
- Brad Nolt,Zhao, Zhijian,Wolkenberg, Scott E.
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p. 3137 - 3141
(2008/09/20)
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- Structure-Activity Relationships of Antibacterial 6,7- and 7,8-Disubstituted 1-Alkyl-1,4-dihydro-4-oxoquinoline-3-carboxylic Acids
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Previous quantitative and qualitative structure-activity studies in antibacterial monosubstituted 1-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acids prompted us to synthesize the 6,7,8-polysubstituted compounds.In this paper, the preparation and antibacterial activity of the 6,7- and 7,8-disubstituted compounds and their derivatives are described.Among these compounds, 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)quinoline-3-carboxylic acid (34) possessed many significant activities and was more active than oxolinic acid (84) against Gram-positive andGram-negative bacteria.Structure activity relationships are discussed.
- Koga, Hiroshi,Itoh, Akira,Murayama, Satoshi,Suzue, Seigo,Irikura, Tsutomu
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p. 1358 - 1363
(2007/10/02)
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