Discovery of TAK-925 as a Potent, Selective, and Brain-Penetrant Orexin 2 Receptor Agonist

Tatsuhiko Fujimoto; Kentaro Rikimaru; Koichiro Fukuda; Hiromichi Sugimoto; Kei Masuda; Norio Ohyabu; Yoshihiro Banno; Norihito Tokunaga; Tetsuji Kawamoto; Yoshihide Tomata; Yasumi Kumagai; Motoo Iida; Yoichi Nagano; Mariko Yoneyama-Hirozane; Yuji Shimizu; Katsunori Sasa; Takashi Ishikawa; Hiroshi Yukitake; Mitsuhiro Ito; Kazunobu Aoyama; Takahiro Matsumoto

doi:10.1021/acsmedchemlett.1c00626

Discovery of TAK-925 as a Potent, Selective, and Brain-Penetrant Orexin 2 Receptor Agonist

ACS Med Chem Lett. 2022 Feb 4;13(3):457-462. doi: 10.1021/acsmedchemlett.1c00626. eCollection 2022 Mar 10.

Authors

Tatsuhiko Fujimoto¹, Kentaro Rikimaru¹, Koichiro Fukuda¹, Hiromichi Sugimoto¹, Kei Masuda¹, Norio Ohyabu¹, Yoshihiro Banno¹, Norihito Tokunaga¹, Tetsuji Kawamoto¹, Yoshihide Tomata¹, Yasumi Kumagai¹, Motoo Iida¹, Yoichi Nagano¹, Mariko Yoneyama-Hirozane¹, Yuji Shimizu¹, Katsunori Sasa¹, Takashi Ishikawa¹, Hiroshi Yukitake¹, Mitsuhiro Ito¹, Kazunobu Aoyama¹, Takahiro Matsumoto¹

Affiliation

¹ Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.

Abstract

TAK-925, a potent, selective, and brain-penetrant orexin 2 receptor (OX2R) agonist, [methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate, 16], was identified through the optimization of compound 2, which was discovered by a high throughput screening (HTS) campaign. Subcutaneous administration of compound 16 produced wake-promoting effects in mice during the sleep phase. Compound 16 (TAK-925) is being developed for the treatment of narcolepsy and other related disorders.