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

We report the discovery of <i>N</i>-substituted 4-(pyridin-2-yl)­thiazole-2-amine derivatives and their subsequent optimization, guided by structure-based design, to give 8-(1<i>H</i>-pyrazol-3-yl)­pyrido­[3,4-<i>d</i>]­pyrimidin-4­(3<i>H</i>)-ones, a series of potent JmjC histone <i>N</i>-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 <b>54j</b> and <b>54k</b> 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 <b>54k</b>, inhibition of H3K9Me₃ and H3K4Me₃ demethylation in a cell-based assay

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

We report the discovery of <i>N</i>-substituted 4-(pyridin-2-yl)­thiazole-2-amine derivatives and their subsequent optimization, guided by structure-based design, to give 8-(1<i>H</i>-pyrazol-3-yl)­pyrido­[3,4-<i>d</i>]­pyrimidin-4­(3<i>H</i>)-ones, a series of potent JmjC histone <i>N</i>-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 <b>54j</b> and <b>54k</b> 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 <b>54k</b>, inhibition of H3K9Me₃ and H3K4Me₃ demethylation in a cell-based assay