Oxadiazole Derivatives as Dual Orexin Receptor Antagonists: Synthesis, Structure-Activity-Relationship, and Sleep-Promoting Properties in the Rat.

Oxadiazole Derivatives as Dual Orexin Receptor Antagonists: Synthesis, Structure-Activity-Relationship, and Sleep-Promoting Properties in the Rat.
ChemMedChem. 2019 May 08;:
Authors: Brotschi C, Roch C, Gatfield J, Treiber A, Williams JT, Sifferlen T, Heidmann B, Jenck F, Bolli MH, Boss C
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 towards a novel DORA. We started our investigation with N-linked benzoxazole 3, a structural hybrid of suvorexant and a piperidine-containing DORA. During the optimization, we resolved liabilities such as chemical instability, CYP-3A4 inhibition, and low brain penetration potential. Furthermore, structural modification of the piperidine-scaffold was essential to improve potency on the orexin 2 receptor. This work led to the identification of (5-methoxy-4-methyl-2-[1,2,3]triazol-2-yl-phenyl)-{(S)-2-[5-(2-trifluoromethoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-pyrrolidin-1-yl}-methanone (51), a potent, brain penetrating DORA with in vivo efficacy comparable to suvorexant in the rat.
PMID: 31066976 [PubMed - as supplied by publisher]

Source: ChemMedChem - May 7, 2019 Category: Chemistry Authors: Brotschi C, Roch C, Gatfield J, Treiber A, Williams JT, Sifferlen T, Heidmann B, Jenck F, Bolli MH, Boss C Tags: ChemMedChem Source Type: research