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1.
Bioorg Med Chem ; 28(13): 115489, 2020 07 01.
Article in English | MEDLINE | ID: mdl-32482533

ABSTRACT

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.


Subject(s)
Orexin Receptor Antagonists/chemical synthesis , Orexin Receptors/metabolism , Orexins/chemistry , Sleep Initiation and Maintenance Disorders/drug therapy , Animals , Dogs , Dose-Response Relationship, Drug , Drug Design , Humans , Male , Molecular Structure , Orexin Receptor Antagonists/pharmacokinetics , Orexins/pharmacokinetics , Rats, Wistar , Sleep/drug effects , Stereoisomerism , Structure-Activity Relationship
2.
Bioorg Med Chem ; 25(20): 5203-5215, 2017 10 15.
Article in English | MEDLINE | ID: mdl-28807572

ABSTRACT

The design, synthesis, and structure activity relationships of the novel class of pyrazolylethylbenzamide orexin receptor 1-selective antagonists are described. Further derivatization of the prototype dual orexin receptor 1/2 antagonist lead (1) by installing a (S)-methyl group into the ethyl linker moiety between the pyrazole ring and benzamide resulted in an increase of the antagonist potency against orexin receptor 1/2 receptors. Optimization of the benzamide and pyrazole parts of compounds 2 and 9b led to the identification of N-ethyl-5-fluoro-N-{(2S)-1-[5-(4-fluorophenyl)-2H-tetrazol-2-yl]propan-2-yl}-2-(pyrimidin-2-yl)benzamide (24), which exhibited excellent antagonistic activity against orexin receptor 1 with an IC50 of 2.01nM and a 265-fold selectivity for orexin receptor 1 over orexin receptor 2.


Subject(s)
Benzamides/pharmacology , Orexin Receptors/metabolism , Pyrazoles/pharmacology , Benzamides/chemical synthesis , Benzamides/chemistry , Dose-Response Relationship, Drug , Humans , Molecular Structure , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Structure-Activity Relationship
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