13631-76-0Relevant articles and documents
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)
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
, p. 3823 - 3841 (2018/05/14)
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 (50 mg) and focused on strategies to increase both ATM potency and predicted human pharmacokinetic half-life (predominantly through the increase of volume of distribution). These efforts resulted in the discovery of 64 (AZD0156), an exceptionally potent and selective inhibitor of ATM based on an imidazo[4,5-c]quinolin-2-one core. 64 has good preclinical phamacokinetics, a low predicted clinical dose, and a high maximum absorbable dose. 64 has been shown to potentiate the efficacy of the approved drugs irinotecan and olaparib in disease relevant mouse models and is currently undergoing clinical evaluation with these agents.
CINNOLIN-4-AMINE COMPOUNDS AND THEIR USE IN TREATING CANCER
-
Page/Page column 43; 55, (2017/10/30)
This specification generally relates to compounds of Formula (I). And pharmaceutically acceptable salts thereof, where R1, R2 and R3 have any of the meanings defined herein. The specification also relates to the use of such compounds and salts thereof to treat or prevent ATM kinase mediated disease, including cancer. The specification further relates to crystalline forms of compounds of Formula (I) and pharmaceutically acceptable salts thereof; pharmaceutical compositions comprising such compounds and salts thereof; kits comprising such compounds and salts thereof; methods of manufacture of such compounds and salts thereof; intermediates useful in the manufacture of such compounds and salts thereof; and to methods of treating ATM kinase mediated disease, including cancer, using compounds of Formula (I) and salts thereof alone or in combination with other therapies.
