Identification and in Vivo Evaluation of Liver X Receptor ?-Selective Agonists for the Potential Treatment of Alzheimer?s Disease [electronic resource]

• Ngôn ngữ: eng
• Ký hiệu phân loại: 512.5 Linear algebra
• Thông tin xuất bản: Argonne, Ill. : Oak Ridge, Tenn. : Argonne National Laboratory ; Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2016
• Mô tả vật lý: Size: p. 3489-3498 : , digital, PDF file.
• Bộ sưu tập: Metadata
• ID: 260933
• Chủ đề: 1. 37 inorganic, organic, physical, and analytical chemistry; 2. 60 applied life sciences; 3. Agonists; 4. Central nervous system; 5. Lipids; 6. Peptides and proteins; 7. Rodent models

Tóm tắt

Herein, we describe the development of a functionally selective liver X receptor ? (LXR?) 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-? peptides were increased concomitantly with an improved peripheral lipid profile relative to that of nonselective compounds. Lastly, 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.