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

  • J Med Chem. 2010 Mar 11;53(5):1923-36. doi: 10.1021/jm9007328.
Bradley R Teegarden  1 ,  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
Affiliations
  • 1. Arena Pharmaceuticals, Inc, 6166 Nancy Ridge Drive, San Diego, California 92121, USA. [email protected]
PMID: 20143782 DOI: 10.1021/jm9007328
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.

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