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.

Abstract

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.

• Authors: Bradley R Teegarden, Hongmei Li, Honnappa Jayakumar, Sonja Strah-Pleynet, Peter I Dosa, Susan D Selaya, Naomi Kato, Katie H Elwell, Jarrod Davidson, Karen Cheng, Hazel Saldana, John M Frazer, Kevin Whelan, Jonathan Foster, Stephan Espitia, Robert R Webb, Nigel R A Beeley, William Thomsen, Stephen R Morairty, Thomas S Kilduff, Hussien A Al-Shamma
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 53 Issue 5 Pg. 1923-36 (Mar 11 2010) ISSN: 1520-4804 [Electronic] United States
• PMID: 20143782 (Publication Type: Journal Article)

Chemical References

• Phenylurea Compounds
• Pyrazoles
• Receptor, Serotonin, 5-HT2A
• Receptor, Serotonin, 5-HT2C
• Serotonin 5-HT2 Receptor Agonists
• Serotonin
• nelotanserin

Topics

• Animals
• Binding, Competitive
• Inhibitory Concentration 50
• Male
• Phenylurea Compounds (chemical synthesis, pharmacokinetics, pharmacology)
• Pyrazoles (chemical synthesis, pharmacokinetics, pharmacology)
• Rats
• Rats, Wistar
• Receptor, Serotonin, 5-HT2A (metabolism)
• Receptor, Serotonin, 5-HT2C (metabolism)
• Serotonin (metabolism)
• Serotonin 5-HT2 Receptor Agonists
• Sleep (drug effects)
• Sleep Initiation and Maintenance Disorders (drug therapy, metabolism)
• Structure-Activity Relationship