8-Substituted Pyrido[3,4-d]pyrimidin-4(3H)-one Derivatives As Potent, Cell Permeable, KDM4 (JMJD2) and KDM5 (JARID1) Histone Lysine Demethylase Inhibitors

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• 作者：Vassilios Bavetsias ; Rachel M. Lanigan ; Gian Filippo Ruda ; Butrus Atrash ; Mark G. McLaughlin ; Anthony Tumber ; N. Yi Mok ; Yann-Vaï Le Bihan ; Sally Dempster ; Katherine J. Boxall ; Fiona Jeganathan ; Stephanie B. Hatch ; Pavel Savitsky ; Srikannathasan Velupillai ; Tobias Krojer ; Katherine S. England ; Jimmy Sejberg ; Ching Thai ; Adam Donovan ; Akos Pal ; Giuseppe Scozzafava ; James M. Bennett ; Akane Kawamura ; Catrine Johansson ; Aleksandra Szykowska ; Carina Gileadi ; Nicola A. Burgess-Brown ; Frank von Delft ; Udo Oppermann ; Zoe Walters ; Janet Shipley ; Florence I. Raynaud ; Susan M. Westaway ; Rab K. Prinjha ; Oleg Fedorov ; Rosemary Burke ; Christopher J. Schofield ; Isaac M. Westwood ; Chas Bountra ; Susanne Müller ; Rob L. M. van Montfort ; Paul E. Brennan ; Julian Blagg
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：February 25, 2016
• 年：2016
• 卷：59
• 期：4
• 页码：1388-1409
• 全文大小：947K
• ISSN：1520-4804

文摘

We report the discovery of N-substituted 4-(pyridin-2-yl)thiazole-2-amine derivatives and their subsequent optimization, guided by structure-based design, to give 8-(1H-pyrazol-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-ones, a series of potent JmjC histone N-methyl lysine demethylase (KDM) inhibitors which bind to Fe(II) in the active site. Substitution from C4 of the pyrazole moiety allows access to the histone peptide substrate binding site; incorporation of a conformationally constrained 4-phenylpiperidine linker gives derivatives such as 54j and 54k which demonstrate equipotent activity versus the KDM4 (JMJD2) and KDM5 (JARID1) subfamily demethylases, selectivity over representative exemplars of the KDM2, KDM3, and KDM6 subfamilies, cellular permeability in the Caco-2 assay, and, for 54k, inhibition of H3K9Me₃ and H3K4Me₃ demethylation in a cell-based assay.