| Literature DB >> 27406798 |
Jun Liang1, Birong Zhang2, Sharada Labadie2, Daniel F Ortwine2, Maia Vinogradova2, James R Kiefer2, Victor S Gehling3, Jean-Christophe Harmange3, Richard Cummings3, Tommy Lai4, Jiangpeng Liao4, Xiaoping Zheng4, Yichin Liu2, Amy Gustafson2, Erica Van der Porten2, Weifeng Mao4, Bianca M Liederer2, Gauri Deshmukh2, Marie Classon2, Patrick Trojer3, Peter S Dragovich2, Lesley Murray2.
Abstract
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=0.34μM). Furthermore, 48 maintained suitable physiochemical properties and displayed an excellent pharmacokinetic (PK) profile in mice. When dosed orally in mice at 50mg/kg twice a day (BID), 48 showed an unbound maximal plasma concentration (Cmax) >15-fold over its cell EC50, thereby providing a robust chemical probe for studying KDM5 biological functions in vivo.Entities:
Keywords: Drug resistance; Epigenetics; Histone demethylase; KDM5; Lead optimization; Selective KDM5 inhibitors
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Year: 2016 PMID： 27406798 DOI： 10.1016/j.bmcl.2016.06.078
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823