Matsuda Takayuki, Okuda Ayumu, Watanabe Yuichiro, Miura Tohru, Ozawa Hidefumi, Tosaka Ayako, Yamazaki Koichi, Yamaguchi Yuki, Kurobuchi Sayaka, Koura Minoru, Shibuya Kimiyuki
Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd, 2-17-43, Noguchicho, Higashimurayam, Tokyo 189-0022, Japan.
Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd, 2-17-43, Noguchicho, Higashimurayam, Tokyo 189-0022, Japan.
Bioorg Med Chem Lett. 2015 Mar 15;25(6):1274-8. doi: 10.1016/j.bmcl.2015.01.047. Epub 2015 Jan 28.
In an attempt to molecularly design liver X receptor (LXR) β-selective agonists, we discovered that the combination of the 2-oxochromene moiety (head) and the imidazoline-2,4-dione moiety (tail) plays an important role in the expression potency and selectivity toward LXRβ. We synthesized a series of 2-oxochromene derivatives and identified 43 as a LXRβ-selective agonist that increased the HDL-C level without significantly elevating the TG level and resulted in a decreased lipid-accumulation area in the aortic arch in a high-fat-and-cholesterol-fed Bio F1B hamster. In this manuscript, we report the design, synthesis and pharmacology of these 2-oxochromene derivatives.
为了从分子层面设计肝脏X受体（LXR）β选择性激动剂，我们发现2-氧代色烯部分（头部）和咪唑啉-2,4-二酮部分（尾部）的组合在对LXRβ的表达效力和选择性方面发挥着重要作用。我们合成了一系列2-氧代色烯衍生物，并确定43号化合物为LXRβ选择性激动剂，它能提高高密度脂蛋白胆固醇（HDL-C）水平，而不会显著升高甘油三酯（TG）水平，并且在高脂高胆固醇喂养的Bio F1B仓鼠中，导致主动脉弓脂质堆积面积减小。在本论文中，我们报告了这些2-氧代色烯衍生物的设计、合成及药理学研究。
