Stachel Shawn J, Zerbinatti Celina, Rudd Michael T, Cosden Mali, Suon Sokreine, Nanda Kausik K, Wessner Keith, DiMuzio Jillian, Maxwell Jill, Wu Zhenhua, Uslaner Jason M, Michener Maria S, Szczerba Peter, Brnardic Edward, Rada Vanessa, Kim Yuntae, Meissner Robert, Wuelfing Peter, Yuan Yang, Ballard Jeanine, Holahan Marie, Klein Daniel J, Lu Jun, Fradera Xavier, Parthasarathy Gopal, Uebele Victor N, Chen Zhongguo, Li Yingjie, Li Jian, Cooke Andrew J, Bennett D Jonathan, Bilodeau Mark T, Renger John
WuXi AppTec Company, Ltd. , Shanghai 200131, P. R. China.
J Med Chem. 2016 Apr 14;59(7):3489-98. doi: 10.1021/acs.jmedchem.6b00176. Epub 2016 Apr 1.
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.
在此，我们描述了一系列功能选择性肝脏X受体β（LXRβ）激动剂的研发情况，这些激动剂针对Emax选择性、溶解度和物理性质进行了优化，以便能够在体内进行疗效和安全性研究。化合物9在啮齿动物模型中显示出中枢药效学作用，这可通过大脑中载脂蛋白E（apoE）和ATP结合盒转运蛋白水平的统计学显著升高得到证明，并且与完全双重激动剂相比，其外周脂质安全性得到了极大改善。这些发现通过在非人类灵长类动物中的亚慢性给药研究得到了重复验证，在这些研究中，相对于非选择性化合物，apoE和淀粉样β肽的脑脊液水平升高，同时外周脂质状况得到改善。这些结果表明，针对Emax选择性优化LXR激动剂可能有潜力规避肝脏LXR活性相关的不良脂质效应。
