Design and synthesis of novel orexin 2 receptor agonists with a 1,3,5‑trioxazatriquinane skeleton.

Mao Amezawa, Naoshi Yamamoto, Yasuyuki Nagumo, Noriki Kutsumura, Yukiko Ishikawa, Masashi Yanagisawa, Hiroshi Nagase, Tsuyoshi Saitoh

Bioorganic & medicinal chemistry letters 2023 Feb 15

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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 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. Copyright © 2023 Elsevier Ltd. All rights reserved.

Citation

Mao Amezawa, Naoshi Yamamoto, Yasuyuki Nagumo, Noriki Kutsumura, Yukiko Ishikawa, Masashi Yanagisawa, Hiroshi Nagase, Tsuyoshi Saitoh. Design and synthesis of novel orexin 2 receptor agonists with a 1,3,5‑trioxazatriquinane skeleton. Bioorganic & medicinal chemistry letters. 2023 Feb 15;82:129151