The Identification of Potent, Selective, and Orally Available Inhibitors of Ataxia Telangiectasia Mutated (ATM) Kinase: The Discovery of AZD0156 (8-{6-[3-(Dimethylamino)propoxy]pyridin-3-yl}-3-methyl-1-(tetrahydro-2 H-pyran-4-yl)-1,3-dihydro-2 H-imidazo[4,5- c]quinolin-2-one)

ATM inhibitors, such as 7, have demonstrated the antitumor potential of ATM inhibition when combined with DNA double-strand break-inducing agents in mouse xenograft models. However, the properties of 7 result in a relatively high predicted clinically efficacious dose. In an attempt to minimize attri...

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Veröffentlicht in:Journal of medicinal chemistry 2018-05, Vol.61 (9), p.3823-3841
Hauptverfasser: Pike, Kurt G, Barlaam, Bernard, Cadogan, Elaine, Campbell, Andrew, Chen, Yingxue, Colclough, Nicola, Davies, Nichola L, de-Almeida, Camila, Degorce, Sebastien L, Didelot, Myriam, Dishington, Allan, Ducray, Richard, Durant, Stephen T, Hassall, Lorraine A, Holmes, Jane, Hughes, Gareth D, MacFaul, Philip A, Mulholland, Keith R, McGuire, Thomas M, Ouvry, Gilles, Pass, Martin, Robb, Graeme, Stratton, Natalie, Wang, Zhenhua, Wilson, Joanne, Zhai, Baochang, Zhao, Kang, Al-Huniti, Nidal
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Sprache:eng
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Zusammenfassung:ATM inhibitors, such as 7, have demonstrated the antitumor potential of ATM inhibition when combined with DNA double-strand break-inducing agents in mouse xenograft models. However, the properties of 7 result in a relatively high predicted clinically efficacious dose. In an attempt to minimize attrition during clinical development, we sought to identify ATM inhibitors with a low predicted clinical dose (
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.7b01896