Synthesis and in vivo evaluation of phenethylpiperazine amides: selective 5-hydroxytryptamine(2A) receptor antagonists for the treatment of insomnia.
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.
Xiong
Yifeng
Y
Arena Pharmaceuticals, San Diego, California 92121, USA. yxiong@arenapharm.com
Ullman
Brett
B
Choi
Jin-Sun Karoline
JS
Cherrier
Martin
M
Strah-Pleynet
Sonja
S
Decaire
Marc
M
Dosa
Peter I
PI
Feichtinger
Konrad
K
Teegarden
Bradley R
BR
Frazer
John M
JM
Yoon
Woo H
WH
Shan
Yun
Y
Whelan
Kevin
K
Hauser
Erin K
EK
Grottick
Andrew J
AJ
Semple
Graeme
G
Al-Shamma
Hussien
H
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
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