Journal
ACS CHEMICAL NEUROSCIENCE
Volume 9, Issue 7, Pages 1625-1636Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.8b00014
Keywords
Multifunctional agents; AChE inhibitors; PDE5 inhibitors; Alzheimer's disease
Funding
- National Key R&D Program of China [2017YFB0202600]
- National Natural Science Foundation of China [21702061, 21672064, 81522045]
- Shanghai Sailing Program [17YF1403600]
- Shu Guang project - Shanghai Municipal Education Commission
- Shanghai Education Development Foundation [14SG28]
- Fundamental Research Funds for the Central Universities
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On the basis of the drug-repositioning and redeveloping strategy, first-generation dual-target inhibitors of acetylcholinesterase (AChE) and phosphodiesterase 5 (PDE5) have been recently reported as a potentially novel therapeutic method for the treatment of Alzheimer's disease (AD), and the lead compound 2 has proven this method was feasible in AD mouse models. In this study, our work focused on exploring alternative novel tadalafil derivatives (3a-s). Among the 19 analogues, compound 3c exhibited good selective dual-target AChE/PDE5 inhibition and good blood-brain barrier (BBB) permeability. Moreover, its citrate (3c center dot Cit) possessed improved water solubility and good effects against scopolamine-induced cognitive impairment with inhibition of cortical AChE activities and enhancement of cAMP response element-binding protein (CREB) phosphorylation ex vivo.
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