title: Synthesis and in vivo evaluation of phenethylpiperazine amides: selective 5-hydroxytryptamine(2A) receptor antagonists for the treatment of insomnia.
abstract: Recent developments in sleep research suggest that antagonism of the serotonin 5-HT(2A) receptor may improve sleep maintenance insomnia. We herein report the discovery of a series of potent and selective serotonin 5-HT(2A) receptor antagonists based on a phenethylpiperazine amide core structure. When tested in a rat sleep pharmacology model, these compounds increased both sleep consolidation and deep sleep. Within this series of compounds, an improvement in the metabolic stability of early leads was achieved by introducing a carbonyl group into the phenethylpiperazine linker. Of note, compounds 14 and 27 exhibited potent 5-HT(2A) receptor binding affinity, high selectivity over the 5-HT(2C) receptor, favorable CNS partitioning, and good pharmacokinetic and early safety profiles. In vivo, these two compounds showed dose-dependent, statistically significant improvements on deep sleep (delta power) and sleep consolidation at doses as low as 0.1 mg/kg.
authors.affiliation: Arena Pharmaceuticals, San Diego, California 92121, USA. yxiong@arenapharm.com
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Xiong
authors.forename: Brett
authors.initials: B
authors.lastname: Ullman
authors.forename: Jin-Sun Karoline
authors.initials: JS
authors.lastname: Choi
authors.forename: Martin
authors.initials: M
authors.lastname: Cherrier
authors.forename: Sonja
authors.initials: S
authors.lastname: Strah-Pleynet
authors.forename: Marc
authors.initials: M
authors.lastname: Decaire
authors.forename: Peter I
authors.initials: PI
authors.lastname: Dosa
authors.forename: Konrad
authors.initials: K
authors.lastname: Feichtinger
authors.forename: Bradley R
authors.initials: BR
authors.lastname: Teegarden
authors.forename: John M
authors.initials: JM
authors.lastname: Frazer
authors.forename: Woo H
authors.initials: WH
authors.lastname: Yoon
authors.forename: Yun
authors.initials: Y
authors.lastname: Shan
authors.forename: Kevin
authors.initials: K
authors.lastname: Whelan
authors.forename: Erin K
authors.initials: EK
authors.lastname: Hauser
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Grottick
authors.forename: Graeme
authors.initials: G
authors.lastname: Semple
authors.forename: Hussien
authors.initials: H
authors.lastname: Al-Shamma
mesh_terms: D000284:Administration, Oral; D000577:Amides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D004285:Dogs; D054314:Drug Inverse Agonism; D000882:Haplorhini; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D010879:Piperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011485:Protein Binding; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D058830:Serotonin 5-HT2 Receptor Antagonists; D012890:Sleep / Q000187:drug effects*; D007319:Sleep Initiation and Maintenance Disorders / Q000188:drug therapy*; D013329:Structure-Activity Relationship
chemical_list: C551952:2-(4-(4-bromo-1-methyl-1H-pyrazole-3-carbonyl)piperazin-1-yl)-1-(4-fluorophenyl)ethanone; C551953:2-(4-(4-chloro-1-methyl-1H-pyrazole-3-carbonyl)piperazin-1-yl)-1-(4-fluorophenyl)ethanone; D000577:Amides; D001798:Blood Proteins; D010879:Piperazines; D011720:Pyrazoles; D058830:Serotonin 5-HT2 Receptor Antagonists