To realize PDE4 inhibitors with good developmental potentiality for the treatment of dementia, structure-based optimizations of lead compound FCPR03 resulted in novel aminophenylketones 9c and 9H with low nanomolar potency, which displayed comparable activity to rolipram, satisfactory bioavailability (F% = 36.92 and 42.96% respectively), and good blood-brain barrier (BBB) permeability switching from the cyclopropyl methoxy group to the cyclopropyl methylamine and the amide group to the corresponding ketone. Emetogenicity evaluation on a combined ketamine/xylazine anesthesia mice alternative model demonstrated that 9H displays no emetogenicity even at an oral dose of 5 mg/kg. In contrast, rolipram and roflumilast displayed emetogenicity at an oral dose of 0.5 mg/kg. In acute toxicological evaluation, 9H showed no obvious toxicological effect on mice when administered at oral doses below 625 mg/kg. Further investigations revealed that 9H improves the memory and cognitive impairment of Alzheimer's disease (AD) model mice induced by Aβ25-35.
Keywords: 3-amino-4-alkoxyphenylketones; PDE4 inhibitors; memory impairments; oral bioavailability; safety.