Alzheimer's Disease (AD) is a debilitating neurodegenerative disorder associated with the death of neurons in brain regions involved in memory, learning and behavior. Novel anti-AD drugs are desperately needed as the incidence of AD is rapidly rising and existing drugs are minimally effective with little, if any, improvement in disease progression. ? ? A central event in the development of AD is the altered processing of amyloid precursor protein (APP) and the subsequent production and aggregation of neurotoxic forms of amyloid b peptide (Ab). Accumulation of Ab aggregates appears to initiate or promote the neuronal degeneration that is characteristic of AD. Therefore, it stands to reason that an ideal molecular target for the treatment of AD is one that can modulate the production and/or accumulation of Ab. A further characteristic of an ideal AD target would be a molecule that is readily """"""""druggable"""""""", i.e. a target that interacts with small drug-like molecules and one that is amenable to high-throughput screening. The nuclear receptor LXR satisfies both requirements as it is modulated by small molecule ligands and has been shown to decrease the production of Ab in cultured cells and in vivo. Reduction in Ab requires an LXR-mediated activation of the cholesterol efflux pump ABCA1. ? ? Two subtypes of LXR have been identified: LXRa and LXRb. The b-subtype is ubiquitously expressed and knockout studies have shown that it is active in the brain. It is this b-subtype which is likely to be the most useful target for decreasing Ab levels. In contrast, the LXRa-subtype is highly expressed in metabolic tissues where it activates expression of SREBP-1c and fatty acid synthase (FAS), thus leading to dramatic elevations in triglyceride levels. This major side-effect has limited the clinical development of non-selective LXRa/b agonists. However, the available evidence suggests that LXRb-selective agonists should be free of this side-effect. In this application we provide the first examples of synthetic LXRb-selective agonists. Using these lead compounds we propose a series of chemical syntheses to optimize this lead and ultimately to test the efficacy of LXRb-selective ligands in vitro and in a mouse model of AD. ? ? ?
