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Abstract
Application WO2012081692 from Taisho Pharmaceutical Co. Ltd. claims pyrazole-based antagonists of the orexin-1 and orexin-2 receptors. Utility in a number of therapeutic areas is claimed, including the treatment of sleep disorders; the most likely use of the claimed compounds. Data from in vitro functional assays are presented, with the claimed compounds typically being dual orexin receptor antagonists (DORAs) or having moderate selectivity for orexin-1. Structurally, the claimed compounds represent a variation on established DORA SAR themes and translate features of clinical compounds into a pyrazole-based scaffold. Example 52, the most potent molecule in the application, has similar molecular weight and lipophilicity to suvorexant, the most advanced DORA, with broadly comparable potency in functional assays.