Through medicinal chemistry lead optimization studies focused on calculated properties and guided by x-ray crystallography and computational modeling, potent JNK inhibitors were identified that showed sub-micromolar activity in a cellular assay. Using in vitro ADME profiling data, 9t was identified as possessing favorable permeability and low potential for efflux, but was rapidly cleared in liver microsomal incubations. In a mouse pharmacokinetic study, compound 9t was brain penetrant after oral dosing, but exposure was limited by high plasma clearance. Brain exposure at a level expected to support modulation of a pharmacodynamic marker in mouse was achieved when the compound was co-administered with the pan-cytochrome P450 inhibitor 1-aminobenzotriazole.

 

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