期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 26, 期 16, 页码 4036-4041出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2016.06.078
关键词
Histone demethylase; KDM5; Selective KDM5 inhibitors; Epigenetics; Drug resistance; Lead optimization
Starting with a lead [1,5-a]pyrimidin-7(4H)-one-containing molecule (1), we generated potent, selective and orally bioavailable KDM5 inhibitors. Using structure- and property-based approaches, we designed 48 with improved cell potency (PC9 H3K4Me3 EC50 = 0.34 mu M). Furthermore, 48 maintained suitable physiochemical properties and displayed an excellent pharmacokinetic (PK) profile in mice. When dosed orally in mice at 50 mg/kg twice a day (BID), 48 showed an unbound maximal plasma concentration (C-max) >15-fold over its cell EC50, thereby providing a robust chemical probe for studying KDM5 biological functions in vivo. (C) 2016 Elsevier Ltd. All rights reserved.
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