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.
Tatsuhiko Fujimoto  1 ,  Kentaro Rikimaru  1 ,  Koichiro Fukuda  1 ,  Hiromichi Sugimoto  1 ,  Kei Masuda  1 ,  Norio Ohyabu  1 ,  Yoshihiro Banno  1 ,  Norihito Tokunaga  1 ,  Tetsuji Kawamoto  1 ,  Yoshihide Tomata  1 ,  Yasumi Kumagai  1 ,  Motoo Iida  1 ,  Yoichi Nagano  1 ,  Mariko Yoneyama-Hirozane  1 ,  Yuji Shimizu  1 ,  Katsunori Sasa  1 ,  Takashi Ishikawa  1 ,  Hiroshi Yukitake  1 ,  Mitsuhiro Ito  1 ,  Kazunobu Aoyama  1 ,  Takahiro Matsumoto  1
Affiliations
  • 1. Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
PMID: 35295087 DOI: 10.1021/acsmedchemlett.1c00626
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.

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