Cell penetrant inhibitors of the KDM4 and KDM5 families of histone lysine demethylases. 2. Pyrido[3,4-d]pyrimidin-4(3H)-one derivatives

Westaway, Susan M. and Preston, Alex G. S. and Barker, Michael D. and Brown, Fiona and Brown, Jack A. and Campbell, Matthew and Chung, Chun-Wa and Drewes, Gerard and Eagle, Robert and Garton, Neil and Gordon, Laurie and Haslam, Carl and Hayhow, Thomas G. and Humphreys, Philip G. and Joberty, Gerard and Katso, Roy and Kruidenier, Laurens and Leveridge, Melanie and Pemberton, Michelle and Rioja, Inma and Seal, Gail A. and Shipley, Tracy and Singh, Onkar and Suckling, Colin J. and Taylor, Joanna and Thomas, Pamela and Wilson, David M. and Lee, Kevin and Prinjha, Rab K. (2016) Cell penetrant inhibitors of the KDM4 and KDM5 families of histone lysine demethylases. 2. Pyrido[3,4-d]pyrimidin-4(3H)-one derivatives. Journal of Medicinal Chemistry, 59 (4). pp. 1370-1387. ISSN 0022-2623

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Abstract

Following the discovery of cell penetrant pyridine-4-carboxylate inhibitors of the KDM4 (JMJD2) and KDM5 (JARID1) families of histone lysine demethylases (e.g., 1), further optimization led to the identification of non-carboxylate inhibitors derived from pyrido[3,4-d]pyrimidin-4(3H)-one. A number of exemplars such as compound 41 possess interesting activity profiles in KDM4C and KDM5C biochemical and target-specific, cellular mechanistic assays.