Discovery of Drugs that Modulate Neuroinflammation for the treatment of Alzheimer's Disease

点击翻译按钮获取中文摘要

Discovery of Drugs that Modulate Neuroinflammation for the Treatment of Alzheimer's Disease Project Summary/Abstract (30 lines) Alzheimer’s disease (AD) is the primary cause of dementia in the elderly. At present, approximately 36 million people worldwide suffer with AD, and that number is expected to increase to about 120 million by 2040. Despite decades of intense research, currently there are only four FDA-approved drugs to treat AD symptoms. These drugs, however, do not prevent, stop or slow the progression of the disease. Inflammation is considered a crucial link between Aβ plaques, NFTs and AD. Therefore, the modulation of pro- inflammatory cytokines may be a viable approach to treat AD. In a screen to identify small molecule modulators of inflammation, we identified a promising lead that has modest affinity for both the GABAA and TSPO receptors. The preliminary SAR and data suggest that the anti-inflammatory effect derives from a combination of both GABAA and TSPO activities. Continued optimization of both the pharmacodynamic and pharmacokinetic properties of the lead will result in a significantly improved molecule that has the potential to treat both (i) cognitive deficits and (ii) anxiety and aggression in AD. The specific aims to achieve this goal are: Aim 1. In vivo proof of concept studies of etifoxine in two mouse models of AD. Etifoxine has demonstrated beneficial effects in several neurodegenerative disease models; however, it was not tested in mouse models of AD or in human AD patients. Therefore, we will evaluate the efficacy of etifoxine in (i) the rTG4510 (Tau pathology) and (ii) the APP/PS1 (amyloid plaque) mouse models of AD. Aim 2. Medicinal chemistry optimization and characterization of novel analogs of etifoxine. Single enantiomer analogs of etifoxine will be designed, synthesized and characterized in biological assays. The most promising compounds will be evaluated in drug-like property and PK studies. Compounds with appropriate PK and brain exposure will advance into in vivo studies to measure target engagement (e.g., stimulation of pregnenolone in mouse brain). Lead compounds also will be tested for sedative effects, and those that have sedative potential will be deprioritized. Aim 3. In vivo efficacy of the lead molecule in the rTG4510 mouse model of AD. We will evaluate the effects of three different doses of the lead compound in the rTG4510 mouse model (as described in Aim 1), Treatment will begin at 2 months (onset pathology), and end at 5 months (start of cognitive decline). The goal is to demonstrate efficacy on multiple measures including inflammation, synaptic integrity, neurodegeneration, tau pathogenesis, memory and learning. Aim 4. Pre-IND enabling studies; scale-up synthesis, multi-species PK, and rodent toxicity. The goal is to determine if the lead compound has any liabilities that would preclude its further development. The lead will be tested in a battery of industry standard in vitro DMPK and in vitro toxicity studies (e.g., CYP inhibition, metabolite identification, and safety panels). Finally, a 10-day, toxicity study will be performed to de-risk the lead compound. 1