Multi-Target Directed Ligands for the Treatment of Alzheimer’s Disease

Abstract

<b>Abstract ID 18315</b> <b>Poster Board 491</b> Alzheimer’s disease (AD) is the most diagnosed neurodegenerative disease, with diagnoses expected to more than double over the next 40 years. Although few treatments are available, current medications have many adverse effects and can treat only mild-to-moderate symptoms in the early stages of AD without altering its progression. The most common AD drugs are acetylcholinesterase (AChE) inhibitors, which increase the activity of acetylcholine concentrations, improving global function. Current research suggests that neuroinflammation plays a significant role in AD pathogenesis. Several recent studies have revealed that the pathophysiology of AD and neuroinflammation involves the two enzymes soluble epoxide hydrolase (sEH) and fatty acid amide hydrolase (FAAH). FAAH is responsible for breaking down anandamide which, when bound to cannabinoid receptors, produces analgesia, anti-inflammation, and neuroprotectant effects. FAAH hydrolases anandamide into arachidonic acid (ARA), an important lipid inflammatory mediator, also produced by the body during inflammation. ARA is further catalyzed to highly anti-inflammatory lipids, epoxy fatty acids (EpFA). In addition to anti-inflammatory activity, EpFAs are known to promote neurogenesis which has the potential to counteract the adverse impact of AD. However, EpFAs are broken down by sEH and produce pro-inflammatory lipids. Furthermore, sEH has been identified as being upregulated in those suffering from AD. Therefore, inhibiting sEH and FAAH represents a novel method of targeting AD pathogenesis. We have previously discovered several potent dual sEH/FAAH inhibitors and showed anti-inflammatory effects in a rat model of acute pain. We hypothesize that simultaneously targeting FAAH, sEH, and AChE enzymes is expected to have significant anti-AD effects. This project aims to develop multi-target directed ligands (MTDLs) or a single small molecule simultaneously operating on all three of the aforementioned biological targets. We previously discovered several potent AChE, FAAH, and sEH inhibitors, with IC₅₀ values of 51 nM, 8 nM, and 10 nM, respectively. In this study, using a polypharmacological strategy, we created three libraries of analogs merging pharmacophores of the three targeted enzymes. We successfully synthesized various analogs and evaluated them in biological enzymatic assays. Surprisingly, most analogs were active in human and rat sEH but not mouse sEH. We identified several AChE/sEH/FAAH inhibitors possessing low micromolar to nanomolar range inhibitory potencies. In addition, several important ADMET predictions were performed, as well as molecular modeling studies. The most promising MTDLs will be further evaluated in an AD rat model. Our studies will provide a foundation for the future investigation of the benefits of using the MTDL strategy in the treatment of multifactorial diseases, such as cancer, pain, and other neurodegenerative diseases.