| Autor: |
Stachel SJ, Zerbinatti C, Rudd MT, Cosden M, Suon S, Nanda KK, Wessner K, DiMuzio J, Maxwell J, Wu Z, Uslaner JM, Michener MS, Szczerba P, Brnardic E, Rada V, Kim Y, Meissner R, Wuelfing P, Yuan Y, Ballard J, Holahan M, Klein DJ, Lu J, Fradera X, Parthasarathy G, Uebele VN, Chen Z; WuXi AppTec Company, Ltd. , Shanghai 200131, P. R. China., Li Y; WuXi AppTec Company, Ltd. , Shanghai 200131, P. R. China., Li J; WuXi AppTec Company, Ltd. , Shanghai 200131, P. R. China., Cooke AJ, Bennett DJ, Bilodeau MT, Renger J |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 2016 Apr 14; Vol. 59 (7), pp. 3489-98. Date of Electronic Publication: 2016 Apr 01. |
| DOI: |
10.1021/acs.jmedchem.6b00176 |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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