Oxadiazole Derivatives as Dual Orexin Receptor Antagonists: Synthesis,Structure–Activity Relationships,and Sleep-Promoting Properties in Rats |
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Authors: | Dr Christine Brotschi Dr Catherine Roch Dr John Gatfield Dr Alexander Treiber Dr Jodi T Williams Dr Thierry Sifferlen Dr Bibia Heidmann Dr Francois Jenck Dr Martin H Bolli Dr Christoph Boss |
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Affiliation: | Drug Discovery and Preclinical Research & Development, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, 4123 Allschwil, BL, Switzerland |
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Abstract: | The orexin system plays an important role in the regulation of wakefulness. Suvorexant, a dual orexin receptor antagonist (DORA) is approved for the treatment of primary insomnia. Herein, we outline our optimization efforts toward a novel DORA. We started our investigation with rac-3-(5-chloro-benzooxazol-2-ylamino)piperidin-1-yl]-(5-methyl-2-1,2,3]triazol-2-ylphenyl)methanone ( 3 ), a structural hybrid of suvorexant and a piperidine-containing DORA. During the optimization, we resolved liabilities such as chemical instability, CYP3A4 inhibition, and low brain penetration potential. Furthermore, structural modification of the piperidine scaffold was essential to improve potency at the orexin 2 receptor. This work led to the identification of (5-methoxy-4-methyl-2-1,2,3]triazol-2-ylphenyl)-{(S)-2-5-(2-trifluoromethoxyphenyl)-1,2,4]oxadiazol-3-yl]pyrrolidin-1-yl}methanone ( 51 ), a potent, brain-penetrating DORA with in vivo efficacy similar to that of suvorexant in rats. |
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Keywords: | drug design dual orexin receptor antagonists insomnia sleep disorders structure–activity relationships |
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