Identification and in Vivo Evaluation of Liver X Receptor β‑Selective Agonists for the Potential Treatment of Alzheimer’s Disease

Herein, we describe the development
of a functionally selective
liver X receptor β (LXRβ) agonist series optimized for
Emax selectivity, solubility, and physical properties to allow efficacy
and safety studies in vivo. Compound 9 showed central
pharmacodynamic effects in rodent models, evidenced by statistically
significant increases in apolipoprotein E (apoE) and ATP-binding cassette
transporter levels in the brain, along with a greatly improved peripheral
lipid safety profile when compared to those of full dual agonists.
These findings were replicated by subchronic dosing studies in non-human
primates, where cerebrospinal fluid levels of apoE and amyloid-β
peptides were increased concomitantly with an improved peripheral
lipid profile relative to that of nonselective compounds. These results
suggest that optimization of LXR agonists for Emax selectivity may
have the potential to circumvent the adverse lipid-related effects
of hepatic LXR activity.