Synthesis and in vivo evaluation of phenethylpiperazine amides: selective 5-hydroxytryptamine(2A) receptor antagonists for the treatment of insomnia.

Abstract

Recent developments in sleep research suggest that antagonism of the serotonin 5-HT(2A) receptor may improve sleep maintenance insomnia. We herein report the discovery of a series of potent and selective serotonin 5-HT(2A) receptor antagonists based on a phenethylpiperazine amide core structure. When tested in a rat sleep pharmacology model, these compounds increased both sleep consolidation and deep sleep. Within this series of compounds, an improvement in the metabolic stability of early leads was achieved by introducing a carbonyl group into the phenethylpiperazine linker. Of note, compounds 14 and 27 exhibited potent 5-HT(2A) receptor binding affinity, high selectivity over the 5-HT(2C) receptor, favorable CNS partitioning, and good pharmacokinetic and early safety profiles. In vivo, these two compounds showed dose-dependent, statistically significant improvements on deep sleep (delta power) and sleep consolidation at doses as low as 0.1 mg/kg.

• Authors: Yifeng Xiong, Brett Ullman, Jin-Sun Karoline Choi, Martin Cherrier, Sonja Strah-Pleynet, Marc Decaire, Peter I Dosa, Konrad Feichtinger, Bradley R Teegarden, John M Frazer, Woo H Yoon, Yun Shan, Kevin Whelan, Erin K Hauser, Andrew J Grottick, Graeme Semple, Hussien Al-Shamma
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 53 Issue 15 Pg. 5696-706 (Aug 12 2010) ISSN: 1520-4804 [Electronic] United States
• PMID: 20684606 (Publication Type: Journal Article)

Chemical References

• 2-(4-(4-bromo-1-methyl-1H-pyrazole-3-carbonyl)piperazin-1-yl)-1-(4-fluorophenyl)ethanone
• 2-(4-(4-chloro-1-methyl-1H-pyrazole-3-carbonyl)piperazin-1-yl)-1-(4-fluorophenyl)ethanone
• Amides
• Blood Proteins
• Piperazines
• Pyrazoles
• Serotonin 5-HT2 Receptor Antagonists

Topics

• Administration, Oral
• Amides (chemical synthesis, pharmacokinetics, pharmacology)
• Animals
• Biological Availability
• Blood Proteins (metabolism)
• Brain (metabolism)
• Dogs
• Drug Inverse Agonism
• Haplorhini
• Humans
• Male
• Microsomes, Liver (metabolism)
• Piperazines (chemical synthesis, pharmacokinetics, pharmacology)
• Protein Binding
• Pyrazoles (chemical synthesis, pharmacokinetics, pharmacology)
• Rats
• Rats, Sprague-Dawley
• Serotonin 5-HT2 Receptor Antagonists
• Sleep (drug effects)
• Sleep Initiation and Maintenance Disorders (drug therapy)
• Structure-Activity Relationship