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

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

  • J Med Chem. 2016 Jul 14;59(13):6281-92. doi: 10.1021/acs.jmedchem.6b00519.
Sébastien L Degorce 1 2,  Bernard Barlaam 1,  Elaine Cadogan 1,  Allan Dishington 1,  Richard Ducray 2,  Steven C Glossop 1,  Lorraine A Hassall 1,  Franck Lach 2,  Alan Lau 1,  Thomas M McGuire 1,  Thorsten Nowak 1,  Gilles Ouvry 2,  Kurt G Pike 1,  Andrew G Thomason 1
Affiliations

Affiliations

  • 1 Oncology Innovative Medicines Unit, AstraZeneca , Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
  • 2 Oncology Innovative Medicines Unit, AstraZeneca, Centre de Recherches , Z.I. la Pompelle, BP 1050, 51689 Reims Cedex 2, France.
PMID: 27259031 DOI: 10.1021/acs.jmedchem.6b00519
Abstract

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.

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