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Liang, Jun; Zhang, Birong; Labadie, Sharada; Ortwine, Daniel F.; Vinogradova, Maia; Kiefer, James R.; Gehling, Victor S.; Harmange, Jean-Christophe; Cummings, Richard; Lai, Tommy; Liao, Jiangpeng; Zheng, Xiaoping; Liu, Yichin; Gustafson, Amy; Van der Porten, Erica; Mao, Weifeng; Liederer, Bianca M.; Deshmukh, Gauri; Classon, Marie; Trojer, Patrick; Dragovich, Peter S.; Murray, Lesley
Bioorganic & medicinal chemistry letters, 08/2016, Letnik: 26, Številka: 16Journal Article
Display omitted Starting with a lead 1,5-apyrimidin-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.
