Design and synthesis of novel orexin 2 receptor agonists with a 1,3,5-trioxazatriquinane skeleton
Design and synthesis of novel orexin 2 receptor agonists with a 1,3,5-trioxazatriquinane skeleton
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具有1,3,5-三氧氮杂三奎烷骨架的新型食欲素2受体激动剂的设计与合成
DOI：
10.1016/j.bmcl.2023.129151
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发表时间：
2023
影响因子：
2.7
通讯作者：
Tsuyoshi Saitoh
中科院分区：
文献类型：
--
作者：
Mao Amezawa;Naoshi Yamamoto;Yasuyuki Nagumo;Noriki Kutsumura;Yukiko Ishikawa;Masashi Yanagisawa;Hiroshi Nagase;Tsuyoshi Saitoh
基于食欲素受体（OXRs）与TriMER型OXR拮抗剂的对接模拟结果，设计并合成了一系列具有氨基-亚甲基侧链的1,3,5 -三恶唑特里醌（TriMER）衍生物。在对食欲素受体的体外筛选中，鉴定出6种具有顺链构型的TriMER衍生物，其中20dand28d在浓度为10µM时对OX2R表现出充分的激动剂活性。为了确定这些hit化合物的绝对立体化学性质，我们还首次以Katsuki-Sharpless不对称环氧化反应为关键反应进行了1,3,5 -三恶唑醌骨架的不对称合成，并获得了一组单独的立体异构体。经活性评价，确定(+)-20d（OX2R EC50= 3.87 μM）和(+)-28d（OX2R EC50= 1.62 μM）为OX2R激动剂活性的自聚体。我们的研究结果提供了一类新的骨架，由(R)-1,3,5 -三恶扎三醌核心与柔性亚甲基连接和侧链末端的疏水取代基组成，氨基甲酸酯/磺胺类化合物作为OX2R激动剂。
A novel series of 1,3,5‑trioxazatriquinane with multiple effective residues (TriMER) derivatives with amino-methylene side chains was designed and synthesized based on the docking-simulation results between orexin receptors (OXRs) and TriMER-type OXR antagonists.In vitroscreening against orexin receptors identified six TriMER derivatives with acisside-chain configuration, and, among these,20dand28dshowed full agonist activity against OX2R at a concentration of 10 µM. To determine the absolute stereochemistry of these hit compounds, we also conducted the first asymmetric synthesis of a 1,3,5‑trioxazatriquinane skeleton using a Katsuki–Sharpless asymmetric epoxidation as the key reaction and obtained a set of the individual stereoisomers. After evaluating their activity, (+)-20d(EC50= 3.87 μM for OX2R) and (+)-28d(EC50= 1.62 μM for OX2R) were determined as eutomers for OX2R agonist activity. Our results provide a new class of skeleton consisting of an (R)-1,3,5‑trioxazatriquinane core with flexible methylene linkers and hydrophobic substituents at the terminals of the side chains via carbamates/sulfonamides as OX2R agonists.