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J Med Chem. 2016 Feb 25;59(4):1357-69. doi: 10.1021/acs.jmedchem.5b01537. Epub 2016 Jan 15.

Cell Penetrant Inhibitors of the KDM4 and KDM5 Families of Histone Lysine Demethylases. 1. 3-Amino-4-pyridine Carboxylate Derivatives.

Author information

1
Epinova Discovery Performance Unit, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
2
Platform Technology and Science, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
3
Cellzome GmbH, a GSK Company , Meyerhofstrasse 1, 69117 Heidelberg, Germany.

Abstract

Optimization of KDM6B (JMJD3) HTS hit 12 led to the identification of 3-((furan-2-ylmethyl)amino)pyridine-4-carboxylic acid 34 and 3-(((3-methylthiophen-2-yl)methyl)amino)pyridine-4-carboxylic acid 39 that are inhibitors of the KDM4 (JMJD2) family of histone lysine demethylases. Compounds 34 and 39 possess activity, IC50 ≤ 100 nM, in KDM4 family biochemical (RFMS) assays with ≥ 50-fold selectivity against KDM6B and activity in a mechanistic KDM4C cell imaging assay (IC50 = 6-8 μM). Compounds 34 and 39 are also potent inhibitors of KDM5C (JARID1C) (RFMS IC50 = 100-125 nM).

PMID:
26771107
DOI:
10.1021/acs.jmedchem.5b01537
[Indexed for MEDLINE]

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