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

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) (-(1-((5-acetylfuran-2-yl)methyl)-1-pyrazol-4-yl)-5-(-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 (OXR) antagonistic activity, stability in liver microsomes, time dependent CYP3A4 inhibition, and aqueous solubility. Compounds were assessed for their brain-penetrating potential in experiments to select the most promising compounds for our sleep model. Our lead optimization efforts led to the discovery of the potent, brain penetrating and orally active, 2-SORA (-(1-(2-(5-methoxy-1-pyrrolo[3,2-]pyridin-3-yl)ethyl)-1-pyrazol-4-yl)-5-(-tolyl)oxazole-4-carboxamide) 43 with efficacy in a sleep model in rats comparable to 15.