TY - JOUR
T1 - Design and synthesis of novel orexin 2 receptor agonists with a 1,3,5‑trioxazatriquinane skeleton
AU - Amezawa, Mao
AU - Yamamoto, Naoshi
AU - Nagumo, Yasuyuki
AU - Kutsumura, Noriki
AU - Ishikawa, Yukiko
AU - Yanagisawa, Masashi
AU - Nagase, Hiroshi
AU - Saitoh, Tsuyoshi
N1 - Funding Information:
This work was financially supported by JSPS KAKENHI grants (18K14352, 19H03428, 20K05743, 21B209 to T.S.; 16H05098, 20H03361 to H.N., Y.N., T.S.), the Japan Foundation for Applied Enzymology (16H007 to T.S.), AMED under grant number JP21zf0127005, Toray Industries, Inc., and a grant for collaborative research between the University of Tsukuba and the Toyota Motor Corporation. IIIS is supported by the World Premier International Research Center Initiative (WPI), Japan.
Publisher Copyright:
© 2023 Elsevier Ltd
PY - 2023/2/15
Y1 - 2023/2/15
N2 - 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.
AB - 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.
KW - 1,3,5-Trioxazatriquinane
KW - Asymmetric synthesis
KW - Orexin receptor
KW - OXR agonist
KW - TriMER
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U2 - 10.1016/j.bmcl.2023.129151
DO - 10.1016/j.bmcl.2023.129151
M3 - Article
C2 - 36690040
AN - SCOPUS:85147227340
SN - 0960-894X
VL - 82
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
M1 - 129151
ER -