Liver X receptors, LXRa and LXRb, are nuclear hormone receptors that function as transcription factors controlling the expression of genes involved in lipid metabolism. Recently studies have demonstrated that agonism of LXR induces up-regulation of apoE and ABCA1, both of which have known genetic deficiencies associated with increased brain amyloid burden in mouse models of Alzheimer's disease. Up-regulation of these genes has been shown to promote amyloid–b peptide (Ab) transport and clearance, thus lowering brain concentrations of amyloid. As such, LXR agonism is emerging as a potential therapeutic approach for Alzheimer's disease. LXR has been investigated for some time as a potential target for the treatment of atherosclerosis, however agonism of LXRa also results in the up-regulation of SREBP1, a master switch for the genes responsible for triglyceride synthesis. As such the development of synthetic LXR ligands as therapeutic agents has been hampered by hepatic steatosis (fatty liver). Our program is based on developing a selective LXRb agonist that increases apoE and ABCA1 without inducing hepatic lipidosis. Optimization of a HTS lead led to the development of an agonist that displayed Emax selectivity for LXRb over LXRa and possessed the required physicochemical properties to facilitate multiday oral. In vivo studies with this agonist in rats and non-human primate showed robust changes in apoE and Ab protein levels with a much improved serum and liver lipid profile when compared with full dual LXR-agonists.

Identification and <i>in vivo</i> evaluation of Liver X receptor b-selective agonists for the potential treatment of Alzheimer's disease

255th National Meeting (2018)

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Identification and in vivo evaluation of Liver X receptor b-selective agonists for the potential treatment of Alzheimer's disease