Cell Penetrant Inhibitors of the KDM4 and KDM5 Families of Histone Lysine Demethylases. 2. Pyrido[3,4‑d]pyrimidin-4(3H)‑one Derivatives

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...

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Veröffentlicht in:	Journal of medicinal chemistry 2016-02, Vol.59 (4), p.1370-1387
Hauptverfasser:	Westaway, Susan M, Preston, Alex G. S, Barker, Michael D, Brown, Fiona, Brown, Jack A, Campbell, Matthew, Chung, Chun-wa, Drewes, Gerard, Eagle, Robert, Garton, Neil, Gordon, Laurie, Haslam, Carl, Hayhow, Thomas G, Humphreys, Philip G, Joberty, Gerard, Katso, Roy, Kruidenier, Laurens, Leveridge, Melanie, Pemberton, Michelle, Rioja, Inma, Seal, Gail A, Shipley, Tracy, Singh, Onkar, Suckling, Colin J, Taylor, Joanna, Thomas, Pamela, Wilson, David M, Lee, Kevin, Prinjha, Rab K
Format:	Artikel
Sprache:	eng
Schlagworte:	Cell Line Cell Membrane Permeability Crystallography, X-Ray Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacokinetics Enzyme Inhibitors - pharmacology Histone Demethylases - antagonists & inhibitors Histone Demethylases - chemistry Histone Demethylases - metabolism Humans Jumonji Domain-Containing Histone Demethylases - antagonists & inhibitors Jumonji Domain-Containing Histone Demethylases - chemistry Jumonji Domain-Containing Histone Demethylases - metabolism Models, Molecular Molecular Docking Simulation Pyrimidinones - chemistry Pyrimidinones - pharmacokinetics Pyrimidinones - pharmacology Structure-Activity Relationship
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Zusammenfassung:	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.
ISSN:	0022-2623 1520-4804
DOI:	10.1021/acs.jmedchem.5b01538