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).

Autor:	Pike KG; Oncology, IMED Biotech Unit , AstraZeneca , Building 310, Cambridge Science Park, 319 Milton Road , Cambridge CB4 0WG , U.K., Barlaam B; Oncology, IMED Biotech Unit , AstraZeneca , Building 310, Cambridge Science Park, 319 Milton Road , Cambridge CB4 0WG , U.K., Cadogan E; Oncology, IMED Biotech Unit , AstraZeneca , Building 310, Cambridge Science Park, 319 Milton Road , Cambridge CB4 0WG , U.K., Campbell A; Pharmaceutical Sciences , AstraZeneca , Silk Road Business Park, Macclesfield SK10 2NA , U.K., Chen Y; Oncology, IMED Biotech Unit , AstraZeneca , 35 Gatehouse Drive , Waltham , Massachusetts 02451 , United States., Colclough N; Oncology, IMED Biotech Unit , AstraZeneca , Building 310, Cambridge Science Park, 319 Milton Road , Cambridge CB4 0WG , U.K., Davies NL; Oncology, IMED Biotech Unit , AstraZeneca , Building 310, Cambridge Science Park, 319 Milton Road , Cambridge CB4 0WG , U.K., de-Almeida C; Oncology, IMED Biotech Unit , AstraZeneca , Building 310, Cambridge Science Park, 319 Milton Road , Cambridge CB4 0WG , U.K., Degorce SL; Oncology, IMED Biotech Unit , AstraZeneca , Building 310, Cambridge Science Park, 319 Milton Road , Cambridge CB4 0WG , U.K.; Oncology, IMED Biotech Unit , AstraZeneca, Centre de Recherches, Z. I. la Pompelle , BP 1050, 51689 Reims Cedex 2 , France., Didelot M; Oncology, IMED Biotech Unit , AstraZeneca, Centre de Recherches, Z. I. la Pompelle , BP 1050, 51689 Reims Cedex 2 , France., Dishington A; Oncology, IMED Biotech Unit , AstraZeneca , Alderley Park , Macclesfield , Cheshire SK10 4TG , U.K., Ducray R; Oncology, IMED Biotech Unit , AstraZeneca, Centre de Recherches, Z. I. la Pompelle , BP 1050, 51689 Reims Cedex 2 , France., Durant ST; Oncology, IMED Biotech Unit , AstraZeneca , Building 310, Cambridge Science Park, 319 Milton Road , Cambridge CB4 0WG , U.K., Hassall LA; Oncology, IMED Biotech Unit , AstraZeneca , Alderley Park , Macclesfield , Cheshire SK10 4TG , U.K., Holmes J; Oncology, IMED Biotech Unit , AstraZeneca , Alderley Park , Macclesfield , Cheshire SK10 4TG , U.K., Hughes GD; Oncology, IMED Biotech Unit , AstraZeneca , Building 310, Cambridge Science Park, 319 Milton Road , Cambridge CB4 0WG , U.K., MacFaul PA; Oncology, IMED Biotech Unit , AstraZeneca , Alderley Park , Macclesfield , Cheshire SK10 4TG , U.K., Mulholland KR; Chemical Development , AstraZeneca , Silk Road Business Park , Macclesfield SK10 2NA , U.K., McGuire TM; Oncology, IMED Biotech Unit , AstraZeneca , Building 310, Cambridge Science Park, 319 Milton Road , Cambridge CB4 0WG , U.K., Ouvry G; Oncology, IMED Biotech Unit , AstraZeneca, Centre de Recherches, Z. I. la Pompelle , BP 1050, 51689 Reims Cedex 2 , France., Pass M; Oncology, IMED Biotech Unit , AstraZeneca , Building 310, Cambridge Science Park, 319 Milton Road , Cambridge CB4 0WG , U.K., Robb G; Oncology, IMED Biotech Unit , AstraZeneca , Building 310, Cambridge Science Park, 319 Milton Road , Cambridge CB4 0WG , U.K., Stratton N; Discovery Sciences , AstraZeneca , Alderley Park , Macclesfield , Cheshire SK10 4TG , U.K., Wang Z; Pharmaron Beijing Co., Ltd. , 6 Taihe Road BDA , Beijing 100176 , P.R. China., Wilson J; Oncology, IMED Biotech Unit , AstraZeneca , Building 310, Cambridge Science Park, 319 Milton Road , Cambridge CB4 0WG , U.K., Zhai B; Pharmaron Beijing Co., Ltd. , 6 Taihe Road BDA , Beijing 100176 , P.R. China., Zhao K; Pharmaron Beijing Co., Ltd. , 6 Taihe Road BDA , Beijing 100176 , P.R. China., Al-Huniti N; Oncology, IMED Biotech Unit , AstraZeneca , 35 Gatehouse Drive , Waltham , Massachusetts 02451 , United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2018 May 10; Vol. 61 (9), pp. 3823-3841. Date of Electronic Publication: 2018 May 02.
DOI:	10.1021/acs.jmedchem.7b01896
Abstrakt:	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.
Databáze:	MEDLINE
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