TY - JOUR
T1 - Discovery of 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl]-3-(2, 4-difluorophenyl)urea (Nelotanserin) and Related 5-Hydroxytryptamine 2A Inverse Agonists for the Treatment of Insomnia
AU - Teegarden, Bradley R.
AU - Li, Hongmei
AU - Jayakumar, Honnappa
AU - Strah-Pleynet, Sonja
AU - Dosa, Peter I.
AU - Selaya, Susan D.
AU - Kato, Naomi
AU - Elwell, Katie H.
AU - Davidson, Jarrod
AU - Cheng, Karen
AU - Saldana, Hazel
AU - Frazer, John M.
AU - Whelan, Kevin
AU - Foster, Jonathan
AU - Espitia, Stephan
AU - Webb, Robert R.
AU - Beeley, Nigel R.A.
AU - Thomsen, William
AU - Morairty, Stephen R.
AU - Kilduff, Thomas S.
AU - Al-Shamma, Hussien A.
PY - 2010/3/11
Y1 - 2010/3/11
N2 - 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-2i/-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.
AB - 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-2i/-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.
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U2 - 10.1021/jm9007328
DO - 10.1021/jm9007328
M3 - Article
C2 - 20143782
AN - SCOPUS:77949420045
SN - 0022-2623
VL - 53
SP - 1923
EP - 1936
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 5
ER -