Chemistry Department, Faculty of Science, Benha University, Benha 13518, Egypt.
Center for Clinical Pharmacology, Washington University School of Medicine and St. Louis College of Pharmacy, St. Louis, MO 63110, USA.
Bioorg Med Chem Lett. 2019 Feb 1;29(3):449-453. doi: 10.1016/j.bmcl.2018.12.025. Epub 2018 Dec 15.
Liver X Receptor (LXR) agonists have been reported as a potential treatment for atherosclerosis, Alzheimer's disease and hepatitis C virus (HCV) infection. We have designed and synthesized a series of potent compounds based on a 1,2,4-triazole scaffold as novel LXR modulators. In cell-based cotransfection assays these compounds generally functioned as LXR agonists and we observed compounds with selectivity towards LXRα (7-fold) and LXRβ (7-fold) in terms of potency. Assessment of the effects of selected compounds on LXR target gene expression in HepG2 cells revealed that compounds 6a-b and 8a-b behaved as inverse agonists on FASN expression even though they were agonists in the LXRα and LXRβ cotransfection assays. Interestingly, these compounds had no effect on the expression of SREBP-1c confirming a unique LXR modulator pharmacology. Molecular docking studies and evaluation of ADME properties in-silico show that active compounds possess favorable binding modes and ADME profiles. Thus, these compounds may be useful for in vivo characterization of LXR modulators with unique profiles and determination of their potential clinical utility.
肝 X 受体 (LXR) 激动剂已被报道可作为动脉粥样硬化、阿尔茨海默病和丙型肝炎病毒 (HCV) 感染的潜在治疗方法。我们设计并合成了一系列基于 1,2,4-三唑骨架的新型 LXR 调节剂。在基于细胞的共转染测定中，这些化合物通常作为 LXR 激动剂起作用，我们观察到在效力方面对 LXRα（7 倍）和 LXRβ（7 倍）具有选择性的化合物。对选定化合物在 HepG2 细胞中对 LXR 靶基因表达的影响进行评估，结果表明，化合物 6a-b 和 8a-b 尽管在 LXRα 和 LXRβ 共转染测定中是激动剂，但对 FASN 表达表现为反向激动剂。有趣的是，这些化合物对 SREBP-1c 的表达没有影响，证实了独特的 LXR 调节剂药理学。分子对接研究和体内评估表明，活性化合物具有有利的结合模式和 ADME 特性。因此，这些化合物可能有助于对具有独特特征的 LXR 调节剂进行体内表征，并确定其潜在的临床用途。
