Lead optimization of apyrazolo[1,5-a]pyrimidin-7(4H)-one scaffold to identify potent, selective and orally bioavailable KDM5 inhibitors suitable for in vivo biological studies

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.