Identification of fused bicyclic heterocycles as potent and selective 5-HT(2A) receptor antagonists for the treatment of insomnia.
A series of fused bicyclic heterocycles was identified as potent and selective 5-HT(2A) receptor antagonists. Optimization of the series resulted in compounds that had improved PK properties, favorable CNS partitioning, good pharmacokinetic properties, and significant improvements on deep sleep (delta power) and sleep consolidation.
Arena Pharmaceuticals Inc., 6166 Nancy Ridge Drive, San Diego, CA 92121, USA. yxiong@arenapharm.com
Yifeng
Y
Xiong
Brett
B
Ullman
Jin-Sun Karoline
JS
Choi
Martin
M
Cherrier
Sonja
S
Strah-Pleynet
Marc
M
Decaire
Konrad
K
Feichtinger
John M
JM
Frazer
Woo H
WH
Yoon
Kevin
K
Whelan
Erin K
EK
Sanabria
Andrew J
AJ
Grottick
Hussien
H
Al-Shamma
Graeme
G
Semple
D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry* / Q000627:therapeutic use*; D006801:Humans; D051381:Rats; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012890:Sleep / Q000187:drug effects*; D007319:Sleep Initiation and Maintenance Disorders / Q000188:drug therapy*; D013329:Structure-Activity Relationship
D019086:Bridged Bicyclo Compounds, Heterocyclic; D044402:Receptor, Serotonin, 5-HT2A; D058830:Serotonin 5-HT2 Receptor Antagonists