Discovery of ORN0829, a potent dual orexin 1/2 receptor antagonist for the treatment of insomnia.

Here, we present the design, synthesis, and SAR of dual orexin 1 and 2 receptor antagonists, which were optimized by balancing the antagonistic activity for orexin receptors and lipophilicity. Based on the prototype compound 1 , ring construction and the insertion of an additional heteroatom into the resulting ring led to the discovery of orexin 1 and 2 receptor antagonists, which were 3-benzoyl-1,3-oxazinane derivatives. Within these derivatives, (−)- 3h enabled a high dual orexin receptor antagonistic activity and a low lipophilicity. Compound (−)- 3h exhibited potent sleep-promoting effects at a po dose of 1 mg/kg in a rat polysomnogram study, and optimal PK properties with a rapid T max and short half-lives in rats and dogs were observed, indicating a predicted human half-life of 0.9–2.0 h. Thus, (−)- 3h (ORN0829 ; investigation code name, TS-142) was selected as a viable candidate and is currently in clinical development for the treatment of insomnia. [ABSTRACT FROM AUTHOR]