1. WBQ5187, a Multitarget Directed Agent, Ameliorates Cognitive Impairment in a Transgenic Mouse Model of Alzheimer's Disease and Modulates Cerebral β-Amyloid, Gliosis, cAMP Levels, and Neurodegeneration.
- Author
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Wang Z, Cao M, Xiang H, Wang W, Feng X, and Yang X
- Subjects
- Alzheimer Disease metabolism, Alzheimer Disease pathology, Anesthetics, General toxicity, Animals, Benzofurans chemistry, Benzofurans pharmacokinetics, Biological Availability, Blood-Brain Barrier, Clioquinol chemistry, Clioquinol pharmacokinetics, Clioquinol therapeutic use, Cyclic AMP metabolism, Disease Models, Animal, Drug Evaluation, Preclinical, Gliosis drug therapy, Gliosis prevention & control, Hippocampus drug effects, Hippocampus metabolism, Male, Maze Learning drug effects, Memory Disorders drug therapy, Memory Disorders genetics, Mice, Mice, Inbred C57BL, Mice, Transgenic, Nausea chemically induced, Neuroprotective Agents chemistry, Neuroprotective Agents pharmacokinetics, Phosphodiesterase 4 Inhibitors chemistry, Phosphodiesterase 4 Inhibitors pharmacokinetics, Phosphodiesterase 4 Inhibitors toxicity, Resorcinols chemistry, Resorcinols pharmacokinetics, Second Messenger Systems drug effects, Vomiting chemically induced, Alzheimer Disease drug therapy, Amyloid beta-Peptides metabolism, Benzofurans therapeutic use, Brain Chemistry drug effects, Clioquinol analogs & derivatives, Neuroprotective Agents therapeutic use, Phosphodiesterase 4 Inhibitors therapeutic use, Resorcinols therapeutic use
- Abstract
Previously, we designed, synthesized, and evaluated a series of quinolone-benzofuran derivatives as multitargeted anti-Alzheimer's disease (anti-AD) compounds, and we discovered that WBQ5187 possesses superior anti-AD bioactivity. In this work, we investigated the pharmacokinetics of this new molecule, as well as its therapeutic efficacy in restoring cognition and neuropathology, in the APP/PS1 mouse model of AD. Pharmacokinetic analyses demonstrated that WBQ5187 possessed rational oral bioavailability, metabolic stability, and excellent blood-brain barrier (BBB) permeability. Pharmacodynamics studies indicated that a 12-week treatment with the lead compound at doses of 40 mg/kg or higher significantly enhanced the learning and memory performance of the APP/PS1 transgenic mice, and the effect was more potent than that of clioquinol (CQ). Furthermore, WBQ5187 notably reduced cerebral β-amyloid pathology, gliosis, and neuronal cell loss and increased the levels of cAMP in the hippocampus of these mice. The surrogate measures of emesis indicated that WBQ5187 had no effect at its cognitive effective doses. Overall, our results demonstrated that this compound markedly improves cognitive and spatial memory functions in AD mice and represents a promising pharmaceutical agent with potential for the treatment of AD.
- Published
- 2019
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