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

[Display omitted] 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 h...

Full description

Saved in:

Bibliographic Details
Published in:	Bioorganic & medicinal chemistry Vol. 28; no. 13; p. 115489
Main Authors:	Futamura, Aya, Suzuki, Ryo, Tamura, Yunoshin, Kawamoto, Hiroshi, Ohmichi, Mari, Hino, Noriko, Tokumaru, Yuichi, Kirinuki, Sora, Hiyoshi, Tetsuaki, Aoki, Takeshi, Kambe, Daiji, Nozawa, Dai
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 01-07-2020
Subjects:	Animals Dogs DORA Dose-Response Relationship, Drug Drug Design Dual orexin receptor antagonist Humans Insomnia Male Molecular Structure Orexin Receptor Antagonists - chemical synthesis Orexin Receptor Antagonists - pharmacokinetics Orexin Receptors - metabolism Orexins - chemistry Orexins - pharmacokinetics Rats, Wistar Sleep - drug effects Sleep Initiation and Maintenance Disorders - drug therapy Stereoisomerism Structure-Activity Relationship PPB SAR Ms CDI CHO PPL MTBE OX1R T3P Boc CSF DORA Cbz CYP RHS Dual orexin receptor antagonist IBX P-gp PSG DIPEA OX2R REMD SORA ER MED Insomnia
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	[Display omitted] 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 Tmax 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.
ISSN:	0968-0896 1464-3391
DOI:	10.1016/j.bmc.2020.115489