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, Yūji Shimizu, Katsunori Sasa, Takashi Ishikawa, Hiroshi Yukitake, Mitsuhiro Ito, Kazunobu Aoyama, Takahiro Matsumoto
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.