Novel multi-target directed ligand-based strategies for reducing neuroinflammation in Alzheimer's disease

摘要

Alzheimer's disease (AD) is one of the most common causes of dementia. AD pathogenesis has been hypothesized to involve cholinergic deficits, amyloid-beta protein (A beta) deposition, tau protein hyperphosphorylation, and chronic neuroinflammation. Many single-target drugs have gone through the various stages of pre-clinical and clinical development in an effort to cure AD; however, the current clinically approved drugs have only limited effects on the disease progression. With the accumulation of unsuccessful clinical trials using single-target drugs, multi-target directed ligand (MTDL) drug development is becoming more common. MTDLs incorporate two or more pharmacophores into a single drug molecule. This approach can alleviate side effects and lead to a better pharmacokinetic profile of the MTDL compared to two or more separate drugs representing respective single pharmacophores. This review discusses cathepsin B (CatB), dual specificity phosphatase 2 (DUSP2), and monoglycerol lipase (MAGL) as targets for MTDLs aimed at slowing down the neuroinflammatory component of neurodegenerative diseases. CatB, DUSP2 and MAGL inhibitors show promising preclinical anti-inflammatory effects in vivo and in vitro. Incorporating pharmacophores that inhibit these targets into MTDLs represents a promising avenue towards effective suppression of neuroinflammation associated with AD.