Cell Penetrant Inhibitors of the KDM4 and KDM5 Families of Histone Lysine Demethylases. 2. Pyrido[3,4-d]pyrimidin-4(3H)-one Derivatives
- J Med Chem. 2016 Feb 25;59(4):1370-87. doi: 10.1021/acs.jmedchem.5b01538.
- 1. Epinova Discovery Performance Unit, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
- 2. Platform Technology and Sciences, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
- 3. Cellzome GmbH, a GSK Company , Meyerhofstrasse 1, 69117 Heidelberg, Germany.
- 4. Department of Pure and Applied Chemistry, WestCHEM Research School, University of Strathclyde , Glasgow G1 1XL, U.K.
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.