The discovery and characterization of a novel chemical series of phosphorothioyl-containing imidazopyridines as potent neuropeptide S receptor antagonists is presented. The synthesis of analogues and their structure-activity relationship with respect to the Gq, Gs, and ERK pathways is detailed. The pharmacokinetics and in vivo efficacy of a potent analogue in a food intake rodent model are also included, underscoring its potential therapeutic value for the treatment of sleep, anxiety, and addiction disorders.

Patnaik, Samarjit; Marugan, Juan; Liu, Ke; Zheng, Wei; Southall, Noel; Dehdashti, Seameen J; Thorsell, Annika; Heilig, Markus; Bell, Lauren; Zook, Michelle; Eskay, Bob; Brimacombe, Kyle; Austin, Christopher;