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


Teegarden, B. R., Li, H., Jayakumar, H., Strah-Pleynet, S., Dosa, P. I., Selaya, S. D., … & Al-Shamma, H. A. (2010). Discovery of 1-[3-(4-Bromo-2-methyl-2 H-pyrazol-3-yl)-4-methoxyphenyl]-3-(2, 4-difluorophenyl) urea (Nelotanserin) and Related 5-Hydroxytryptamine2A Inverse Agonists for the Treatment of Insomnia. Journal of medicinal chemistry, 53(5), 1923-1936.


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.

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