Details

Autor(en) / Beteiligte

• Teegarden, Bradley R
• Li, Hongmei
• Jayakumar, Honnappa
• Strah-Pleynet, Sonja
• Dosa, Peter I
• Selaya, Susan D
• Kato, Naomi
• Elwell, Katie H
• Davidson, Jarrod
• Cheng, Karen
• Saldana, Hazel
• Frazer, John M
• Whelan, Kevin
• Foster, Jonathan
• Espitia, Stephan
• Webb, Robert R
• Beeley, Nigel R. A
• Thomsen, William
• Morairty, Stephen R
• Kilduff, Thomas S
• Al-Shamma, Hussien A

Titel

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

Ist Teil von

• Journal of medicinal chemistry, 2010-03, Vol.53 (5), p.1923-1936

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2010

Quelle

MEDLINE

Beschreibungen/Notizen

• 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-hydroxytryptamine2A (5-HT2A) receptor, serotonin (5-HT) plays a role in the regulation of sleep architecture, and antagonists/inverse-agonists of 5-HT2A have been shown to enhance slow wave sleep (SWS). We describe here a series of 5-HT2A 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-HT2A that was advanced into clinical trials for the treatment of insomnia.