Discovery of 1-[3-(4-bromo-2-methyl-2h-pyrazol-3-yl)-4-methoxyphenyl]-3-(2,4-difluorophenyl)urea (nelotanserin) and related 5-hydroxytryptamine2A inverse agonists for the treatment of insomnia.
Insomnia affects a growing portion of the adult population in the U.S. Most current therapeutic approaches to insomnia primarily address sleep onset latency. Through the 5-hydroxytryptamine(2A) (5-HT(2A)) receptor, serotonin (5-HT) plays a role in the regulation of sleep architecture, and antagonists/inverse-agonists of 5-HT(2A) have been shown to enhance slow wave sleep (SWS). We describe here a series of 5-HT(2A) inverse-agonists that when dosed in rats, both consolidate the stages of NREM sleep, resulting in fewer awakenings, and increase a physiological measure of sleep intensity. These studies resulted in the discovery of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl]-3-(2,4-difluorophenyl)urea (Nelotanserin), a potent inverse-agonist of 5-HT(2A) that was advanced into clinical trials for the treatment of insomnia.
Teegarden
Bradley R
BR
Arena Pharmaceuticals, Inc, 6166 Nancy Ridge Drive, San Diego, California 92121, USA. bradteegarden@ymail.com
Li
Hongmei
H
Jayakumar
Honnappa
H
Strah-Pleynet
Sonja
S
Dosa
Peter I
PI
Selaya
Susan D
SD
Kato
Naomi
N
Elwell
Katie H
KH
Davidson
Jarrod
J
Cheng
Karen
K
Saldana
Hazel
H
Frazer
John M
JM
Whelan
Kevin
K
Foster
Jonathan
J
Espitia
Stephan
S
Webb
Robert R
RR
Beeley
Nigel R A
NR
Thomsen
William
W
Morairty
Stephen R
SR
Kilduff
Thomas S
TS
Al-Shamma
Hussien A
HA
D000818:Animals; D001667:Binding, Competitive; D020128:Inhibitory Concentration 50; D008297:Male; D010671:Phenylurea Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D058826:Serotonin 5-HT2 Receptor Agonists; D012890:Sleep / Q000187:drug effects; D007319:Sleep Initiation and Maintenance Disorders / Q000188:drug therapy* / Q000378:metabolism; D013329:Structure-Activity Relationship
D010671:Phenylurea Compounds; D011720:Pyrazoles; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D058826:Serotonin 5-HT2 Receptor Agonists; D012701:Serotonin; C546600:nelotanserin