Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8571, Japan.
International Institute for Integrative Sleep Medicine (IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
Bioorg Med Chem Lett. 2023 Feb 15;82:129151. doi: 10.1016/j.bmcl.2023.129151. Epub 2023 Jan 20.
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 vitro screening against orexin receptors identified six TriMER derivatives with a cis side-chain configuration, and, among these, 20d and 28d showed full agonist activity against OXR 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 (EC = 3.87 μM for OXR) and (+)-28d (EC = 1.62 μM for OXR) were determined as eutomers for OXR 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 OXR agonists.
基于食欲素受体（OXRs）与三嗪三嗪型 OXR 拮抗剂之间的对接模拟结果，设计并合成了一系列具有多个有效残基的新型 1,3,5-三恶嗪三嗪衍生物（TriMER），带有氨基亚甲基侧链。对食欲素受体的体外筛选鉴定出了 6 种具有顺式侧链构型的 TriMER 衍生物，其中，化合物 20d 和 28d 在 10µM 浓度下对 OXR 表现出完全激动剂活性。为了确定这些命中化合物的绝对立体化学，我们还首次使用 Katsuki-Sharpless 不对称环氧化作为关键反应对 1,3,5-三恶嗪三嗪骨架进行了不对称合成，并获得了一组单个的立体异构体。在评估其活性后，(+)-20d（OXR 的 EC = 3.87µM）和(+)-28d（OXR 的 EC = 1.62µM）被确定为 OXR 激动剂活性的优势对映异构体。我们的结果提供了一类新的骨架，该骨架由（R）-1,3,5-三恶嗪三嗪核心组成，带有柔性亚甲基连接体和侧链末端的疏水性取代基，通过氨基甲酸酯/磺酰胺作为 OXR 激动剂。
