Journal of Medicinal Chemistry p. 6281 - 6292 (2016)
Update date:2022-08-05
Topics:
Degorce, Sébastien L.
Barlaam, Bernard
Cadogan, Elaine
Dishington, Allan
Ducray, Richard
Glossop, Steven C.
Hassall, Lorraine A.
Lach, Franck
Lau, Alan
McGuire, Thomas M.
Nowak, Thorsten
Ouvry, Gilles
Pike, Kurt G.
Thomason, Andrew G.
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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