Essential structure of orexin 1 receptor antagonist YNT-707, part V: Structure-activity relationship study of the substituents on the 17-amino group

Tsuyoshi Saitoh; Kazunori Seki; Ryo Nakajima; Naoshi Yamamoto; Noriki Kutsumura; Yasuyuki Nagumo; Yoko Irukayama-Tomobe; Yasuhiro Ogawa; Yukiko Ishikawa; Masashi Yanagisawa; Hiroshi Nagase

doi:10.1016/j.bmcl.2019.126893

Essential structure of orexin 1 receptor antagonist YNT-707, part V: Structure-activity relationship study of the substituents on the 17-amino group

Bioorg Med Chem Lett. 2020 Feb 1;30(3):126893. doi: 10.1016/j.bmcl.2019.126893. Epub 2019 Dec 17.

Affiliations

¹ International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
² Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8571, Japan.
³ International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan; R&D Center for Frontiers of Mirai in Policy and Technology (F-MIRAI), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan; Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States.
⁴ International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan; Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8571, Japan. Electronic address: [email protected].

PMID: 31879208
DOI: 10.1016/j.bmcl.2019.126893

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 (K_i = 14.8 nM).

Keywords: Nalfurafine; Orexin; Ring removal; Substituent effect; YNT-707.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amines / chemistry
Humans
Kinetics
Morphinans / chemistry*
Morphinans / metabolism
Orexin Receptor Antagonists / chemical synthesis
Orexin Receptor Antagonists / chemistry*
Orexin Receptor Antagonists / metabolism
Orexin Receptors / chemistry*
Orexin Receptors / metabolism
Structure-Activity Relationship
Sulfonamides / chemistry*
Sulfonamides / metabolism

Substances

Amines
Morphinans
Orexin Receptor Antagonists
Orexin Receptors
Sulfonamides
YNT-707