@article{7d00af17f1f8440a8804519c1ab9a4d6,
title = "Essential structure of orexin 1 receptor antagonist YNT-707, part V: Structure-activity relationship study of the substituents on the 17-amino group",
abstract = "The morphinan-type orexin 1 receptor (OX1R) antagonists such as YNT-707 (2) and YNT-1310 (3) show potent and extremely high selective antagonistic activity against OX1R. In the course of our studies of the essential structure of 2, we identified new scaffolds by simplification of the morphinan skeleton. However, the new chemical entities carrying the D-ring removed scaffold showed insufficient activity. To improve the activity of these derivatives, we investigated the effect of substituents mainly focused on the 17-nitrogen group. The 17-N-substituted derivatives, as well as the cyclic derivatives, were synthesized and examined the OX1R antagonistic activity. The assay results showed the interesting relationship between the OX1R antagonistic activity and the substituents on the 17-nitrogen: the antagonistic activity was increased as the bulkiness of 17-substituents increased. Finally, the 17-N-Boc derivative 14a showed the most potent OX1R antagonistic activity (Ki = 14.8 nM).",
keywords = "Nalfurafine, Orexin, Ring removal, Substituent effect, YNT-707",
author = "Tsuyoshi Saitoh and Kazunori Seki and Ryo Nakajima and Naoshi Yamamoto and Noriki Kutsumura and Yasuyuki Nagumo and Yoko Irukayama-Tomobe and Yasuhiro Ogawa and Yukiko Ishikawa and Masashi Yanagisawa and Hiroshi Nagase",
note = "Funding Information: This work was supported by JSPS KAKENHI ( 15K16557 , 18K14352 to T.S.; 16H05098 to H.N., Y.I-T., T.S.; 18K11014 to Y.I-T., T.S.; 19K07314 to Y.I-T.), MEXT Grant-in-Aid for Scientific Research on Innovative Areas ( JP15H05942 “LivinginSpace” to H.N.; JP17H06049 “Willdynamics” to Y.I-T.), Japan Foundation, Japan for Applied Enzymology ( 16H007 to T.S.) and Toray Industries , Inc. IIIS is also supported by the World Premier International Research Center (WPI) Initiative, Japan. Funding Information: This work was supported by JSPS KAKENHI (15K16557, 18K14352 to T.S.; 16H05098 to H.N. Y.I-T. T.S.; 18K11014 to Y.I-T. T.S.; 19K07314 to Y.I-T.), MEXT Grant-in-Aid for Scientific Research on Innovative Areas (JP15H05942 “LivinginSpace” to H.N.; JP17H06049 “Willdynamics” to Y.I-T.), Japan Foundation, Japan for Applied Enzymology (16H007 to T.S.) and Toray Industries, Inc. IIIS is also supported by the World Premier International Research Center (WPI) Initiative, Japan. Publisher Copyright: {\textcopyright} 2019 Elsevier Ltd",
year = "2020",
month = feb,
day = "1",
doi = "10.1016/j.bmcl.2019.126893",
language = "English (US)",
volume = "30",
journal = "Bioorganic and Medicinal Chemistry Letters",
issn = "0960-894X",
publisher = "Elsevier Limited",
number = "3",
}