Discovery of Novel 3-Quinoline Carboxamides as Potent, Selective, and Orally Bioavailable Inhibitors of Ataxia Telangiectasia Mutated (ATM) Kinase.

Autor:	Degorce SL; Oncology Innovative Medicines Unit, AstraZeneca , Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.; Oncology Innovative Medicines Unit, AstraZeneca, Centre de Recherches , Z.I. la Pompelle, BP 1050, 51689 Reims Cedex 2, France., Barlaam B; Oncology Innovative Medicines Unit, AstraZeneca , Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom., Cadogan E; Oncology Innovative Medicines Unit, AstraZeneca , Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom., Dishington A; Oncology Innovative Medicines Unit, AstraZeneca , Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom., Ducray R; Oncology Innovative Medicines Unit, AstraZeneca, Centre de Recherches , Z.I. la Pompelle, BP 1050, 51689 Reims Cedex 2, France., Glossop SC; Oncology Innovative Medicines Unit, AstraZeneca , Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom., Hassall LA; Oncology Innovative Medicines Unit, AstraZeneca , Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom., Lach F; Oncology Innovative Medicines Unit, AstraZeneca, Centre de Recherches , Z.I. la Pompelle, BP 1050, 51689 Reims Cedex 2, France., Lau A; Oncology Innovative Medicines Unit, AstraZeneca , Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom., McGuire TM; Oncology Innovative Medicines Unit, AstraZeneca , Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom., Nowak T; Oncology Innovative Medicines Unit, AstraZeneca , Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom., Ouvry G; Oncology Innovative Medicines Unit, AstraZeneca, Centre de Recherches , Z.I. la Pompelle, BP 1050, 51689 Reims Cedex 2, France., Pike KG; Oncology Innovative Medicines Unit, AstraZeneca , Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom., Thomason AG; Oncology Innovative Medicines Unit, AstraZeneca , Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2016 Jul 14; Vol. 59 (13), pp. 6281-92. Date of Electronic Publication: 2016 Jun 16.
DOI:	10.1021/acs.jmedchem.6b00519
Abstrakt:	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.
Databáze:	MEDLINE
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