1. 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-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one)
- Author
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Camila de-Almeida, Keith R. Mulholland, Kang Zhao, Barlaam Bernard Christophe, Gilles Ouvry, Gareth Hughes, Martin Pass, Elaine Cadogan, Zhenhua Wang, Andrew D. Campbell, Nidal Al-Huniti, Natalie Stratton, Sébastien L. Degorce, Joanne Wilson, Myriam Didelot, Philip A. MacFaul, Stephen T. Durant, Richard Ducray, Baochang Zhai, Kurt Gordon Pike, Lorraine A. Hassall, Jane L. Holmes, Thomas M. McGuire, Nichola L. Davies, Allan Dishington, Yingxue Chen, Nicola Colclough, and Graeme R. Robb
- Subjects
Models, Molecular ,0301 basic medicine ,Protein Conformation ,Pyridines ,Administration, Oral ,Biological Availability ,Ataxia Telangiectasia Mutated Proteins ,Quinolones ,Pharmacology ,Substrate Specificity ,Olaparib ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Pharmacokinetics ,Drug Discovery ,medicine ,Humans ,Structure–activity relationship ,Potency ,Protein Kinase Inhibitors ,Volume of distribution ,Chemistry ,Atm kinase ,Irinotecan ,030104 developmental biology ,Pyran ,Drug Design ,030220 oncology & carcinogenesis ,Quinolines ,Molecular Medicine ,medicine.drug - Abstract
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.
- Published
- 2018
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