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

Abstract Starting with a lead [1,5- a ]pyrimidin-7(4 H )-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 EC 50  = 0.34 μM). 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 EC 50 , thereby providing a robust chemical probe for studying KDM5 biological functions in vivo.