Pyrazole derivatives as selective orexin-2 receptor antagonists (2-SORA): synthesis, structure-activity-relationship, and sleep-promoting properties in rats.

ABSTRACT: Selective orexin 2 receptor antagonists (2-SORA) such as seltorexant (15) are in clinical development for the treatment of insomnia and other conditions such as depression. Herein, we report our structure-activity-relationship (SAR) optimization efforts starting from an HTS hit (1) (N-(1-((5-acetylfuran-2-yl)methyl)-1H-pyrazol-4-yl)-5-(m-tolyl)oxazole-4-carboxamide) that was derived from an unrelated in-house GPCR-agonist program. Medicinal chemistry efforts focused on the optimization of orexin 2 receptor (OX₂R) antagonistic activity, stability in liver microsomes, time dependent CYP3A4 inhibition, and aqueous solubility. Compounds were assessed for their brain-penetrating potential in in vivo experiments to select the most promising compounds for ou

SUBMITTER: Brotschi C 

PROVIDER: S-EPMC10809354 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature