Identification of fused bicyclic heterocycles as potent and selective 5-HT(2A) receptor antagonists for the treatment of insomnia

Yifeng Xiong; Brett Ullman; Jin-Sun Karoline Choi; Martin Cherrier; Sonja Strah-Pleynet; Marc Decaire; Konrad Feichtinger; John M Frazer; Woo H Yoon; Kevin Whelan; Erin K Sanabria; Andrew J Grottick; Hussien Al-Shamma; Graeme Semple

doi:10.1016/j.bmcl.2012.01.080

Identification of fused bicyclic heterocycles as potent and selective 5-HT(2A) receptor antagonists for the treatment of insomnia

Bioorg Med Chem Lett. 2012 Mar 1;22(5):1870-3. doi: 10.1016/j.bmcl.2012.01.080. Epub 2012 Jan 28.

Authors

Yifeng Xiong¹, Brett Ullman, Jin-Sun Karoline Choi, Martin Cherrier, Sonja Strah-Pleynet, Marc Decaire, Konrad Feichtinger, John M Frazer, Woo H Yoon, Kevin Whelan, Erin K Sanabria, Andrew J Grottick, Hussien Al-Shamma, Graeme Semple

Affiliation

¹ Arena Pharmaceuticals Inc., 6166 Nancy Ridge Drive, San Diego, CA 92121, USA. yxiong@arenapharm.com

PMID: 22325948
DOI: 10.1016/j.bmcl.2012.01.080

Abstract

A series of fused bicyclic heterocycles was identified as potent and selective 5-HT(2A) receptor antagonists. Optimization of the series resulted in compounds that had improved PK properties, favorable CNS partitioning, good pharmacokinetic properties, and significant improvements on deep sleep (delta power) and sleep consolidation.

MeSH terms

Animals
Bridged Bicyclo Compounds, Heterocyclic / chemistry*
Bridged Bicyclo Compounds, Heterocyclic / therapeutic use*
Humans
Rats
Receptor, Serotonin, 5-HT2A / metabolism*
Serotonin 5-HT2 Receptor Antagonists / chemistry*
Serotonin 5-HT2 Receptor Antagonists / pharmacokinetics
Serotonin 5-HT2 Receptor Antagonists / therapeutic use*
Sleep / drug effects*
Sleep Initiation and Maintenance Disorders / drug therapy*
Structure-Activity Relationship

Substances

Bridged Bicyclo Compounds, Heterocyclic
Receptor, Serotonin, 5-HT2A
Serotonin 5-HT2 Receptor Antagonists