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.

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In this study we observed the inhibitory effect of Chinese herbal medicine Ganoderma lucidum (GL) on platelet aggregation in 15 healthy volunteers and 33 patients with atherosclerotic diseases. The results showed that the first and the second phase of aggregation of platelets of the healthy volunteers were obviously inhibited (P less than 0.01) when watery soluble extract of GL of different concentrations was added to the platelets in vitro, i. e., the reaction speed of platelet aggregation was slowed down. The inhibitory effect was related to dosage. Platelet aggregation induced by ADP in final concentration of 2 mumol/L and 3 mumol/L was obviously inhibited, after the patients had taken GL 1 g 3 times a day for 2 weeks, the maximum platelet aggregation inhibition rates were then 31.49% (P less than 0.01) and 17.7% (P less than 0.01) respectively. Length and weights (wet and dry) of the extracorporeal thrombi were reduced from 30.05 +/- 4.38 mm, 103.9 +/- 9.33 mg and 44.89 +/- 4.79 mg to 20.4 +/- 2.33 mm (P less than 0.05), 85.27 +/- 8.77 mg (P less than 0.01) and 35.1 +/- 4.5 mg (P less than 0.01) respectively after oral administration of GL. The results of our experiments suggested that the Chinese herbal medicine GL may be an effective inhibitory agent of platelet aggregation. However, its mechanism and active principles remain to be further investigated.

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