Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 59, Issue 7, Pages 3489-3498Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.6b00176
Keywords
-
Categories
Ask authors/readers for more resources
Herein, we describe the development of a functionally selective liver X receptor beta (LXR beta) 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-beta 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available