Drug Development of Novel PDE5 Inhibitors Against Alzheimer's disease

Background Nerve cells in the brain 'talk' to each other through specialized structures called synapses. Synapses connect one nerve cell to another, creating extensive nerve cell networks. In Alzheimer's, synapses may be damaged and this may impair nerve cell communication in the brain, which could be associated with memory loss and cognitive decline. Studies show that an enzyme (substance or chemical produced by the body to regulate biochemical reactions) in the brain, called phosphodiesterase 5 (PDE5) involved in a chain of nerve cell signaling events may be associated with damage to synapses in Alzheimer's. Researchers have shown that blocking PDE5 may impact memory in aged mice and in genetically engineered Alzheimer's-like mice. However, current compounds that block PDE5 may be unable to cross into the blood brain barrier - a specialized structure that is a highly selective barrier to help maintain a healthy brain environment by tightly regulating what goes in and out of the brain from the circulating blood. In preliminary studies, Dr. Elisa Zuccarello and colleagues have tested chemical compounds to block PDE5 and found a candidate compound that may be able to enter the brain in mice. The researchers the compound may also impact memory in genetically engineered Alzheimer's-like mice. Furthermore, Dr. Zuccarello and colleagues have refined their techniques to develop two new compounds derived from their original compound. Research Plan Building on their preliminary studies and using medicinal chemistry approaches, Dr. Zuccarello and colleagues will optimize their original candidate compound and the two derivatives of the original compound. The researchers will test the effectiveness of their compounds in being able to enter the brain and block PDE5 in genetically engineered Alzheimer's-like mice. The researchers will then study whether these compounds may be able to impact brain activity and memory in the Alzheimer's-like mice. Dr. Zuccarello believes that based on these experiments, they may be able to identify an optimal candidate for further testing including its impact on cognitive decline in the Alzheimer's-like mice. Impact The study results may help understand whether compounds that block PDE5 and cross into the brain may impact brain changes observed in Alzheimer's. If successful, the findings may lead to the identification of potential candidate compounds for clinical trials.