Discovery of 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl]-3-(2,4-difluoro phenyl)urea (Nelotanserin) and Related 5-Hydroxytryptamine(2A) Inverse Agonists for the Treatment of Insomnia

摘要

Insomnia affects it 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-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-difluoro phenyl)urea (Nelotanserin), it potent inverse-agonist of 5-HT2A that was advanced into clinical trials for the treatment of insomnia.