Discovery and optimisation of 1-acyl-2-benzylpyrrolidines as potent dual orexin receptor antagonists Electronic supplementary information (ESI) available. See DOI: 10.1039/c5md00074b

Starting from a thienopiperidine lead compound with high intrinsic clearance in rat and human liver microsomes and low aqueous solubility, a novel series of 1-acyl-2-benzylpyrrolidines were discovered as potent and competitive dual orexin receptor antagonists. Metabolic stability was improved to afford oral exposure, and aqueous solubility was increased by twentyfold, providing compounds suitable for preclinical evaluation. Compound 27 showed insurmountable antagonism at both orexin 1 and orexin 2 receptor subtypes and displayed a comparable sleep-promoting effect in the rat to almorexant and suvorexant. The evolution of our lead compound 1 into the in vivo active, competitive, dual orexin receptor antagonist 27 , is described.