Identification of highly selective and potent orexin receptor 1 antagonists derived from a dual orexin receptor 1/2 antagonist based on the structural framework of pyrazoylethylbenzamide

Publication date: 15 October 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 20
Author(s): Aya Futamura, Dai Nozawa, Yuko Araki, Yunoshin Tamura, Seiken Tokura, Hiroshi Kawamoto, Yuichi Tokumaru, Sora Kakihara, Takeshi Aoki, Norikazu Ohtake
The design, synthesis, and structure activity relationships of the novel class of pyrazolylethylbenzamide orexin receptor 1-selective antagonists are described. Further derivatization of the prototype dual orexin receptor 1/2 antagonist lead (1) by installing a (S)-methyl group into the ethyl linker moiety between the pyrazole ring and benzamide resulted in an increase of the antagonist potency against orexin receptor 1/2 receptors. Optimization of the benzamide and pyrazole parts of compounds 2 and 9b led to the identification of N-ethyl-5-fluoro-N-{(2S)-1-[5-(4-fluorophenyl)-2H-tetrazol-2-yl]propan-2-yl}-2-(pyrimidin-2-yl)benzamide (24), which exhibited excellent antagonistic activity against orexin receptor 1 with an IC50 of 2.01nM and a 265-fold selectivity for orexin receptor 1 over orexin receptor 2.

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