Journal of Medicinal Chemistry p. 1388 - 1409 (2016)
Update date:2022-08-16
Topics:
Bavetsias, Vassilios
Lanigan, Rachel M.
Ruda, Gian Filippo
Atrash, Butrus
McLaughlin, Mark G.
Tumber, Anthony
Mok, N. Yi
Le Bihan, Yann-Va?
Dempster, Sally
Boxall, Katherine J.
Jeganathan, Fiona
Hatch, Stephanie B.
Savitsky, Pavel
Velupillai, Srikannathasan
Krojer, Tobias
England, Katherine S.
Sejberg, Jimmy
Thai, Ching
Donovan, Adam
Pal, Akos
Scozzafava, Giuseppe
Bennett, James M.
Kawamura, Akane
Johansson, Catrine
Szykowska, Aleksandra
Gileadi, Carina
Burgess-Brown, Nicola A.
Von Delft, Frank
Oppermann, Udo
Walters, Zoe
Shipley, Janet
Raynaud, Florence I.
Westaway, Susan M.
Prinjha, Rab K.
Fedorov, Oleg
Burke, Rosemary
Schofield, Christopher J.
Westwood, Isaac M.
Bountra, Chas
Müller, Susanne
Van Montfort, Rob L. M.
Brennan, Paul E.
Blagg, Julian
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.
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Doi:10.1021/acs.orglett.9b02139
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(2021)Doi:10.1021/ja01314a069
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