Design and synthesis of novel orexin 2 receptor agonists with a 1, 3, 5‑trioxazatriquinane skeleton. (15th February 2023)

• Record Type: Journal Article
• Authors: Amezawa, Mao; Yamamoto, Naoshi; Nagumo, Yasuyuki; Kutsumura, Noriki; Ishikawa, Yukiko; Yanagisawa, Masashi; Nagase, Hiroshi; Saitoh, Tsuyoshi
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 82(2023)
• Publication Date: 2023-02-15
• Subjects: Orexin receptor -- OX2R agonist -- 1, 3, 5-Trioxazatriquinane -- TriMER -- Asymmetric synthesis; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2023.129151
• Languages: English
• ISSNs: 0960-894X

Abstract

Abstract: 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 OX2 R 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 OX2 R) and ( + )-28d (EC50 = 1.62 μM for OX2 R) were determined as eutomers for OX2 R 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 OX2 R agonists.