Synthesis and in vivo evaluation of phenethylpiperazine amides: selective 5-hydroxytryptamine(2A) receptor antagonists for the treatment of insomnia
| Autor: | Marc Decaire, Woo H. Yoon, Sonja Strah-Pleynet, Martin C. Cherrier, Yifeng Xiong, Andrew J. Grottick, Yun Shan, Konrad Feichtinger, Jin-Sun Karoline Choi, Peter I. Dosa, Erin K. Hauser, Graeme Semple, Bradley Teegarden, Brett Ullman, Hussien A. Al-Shamma, John Frazer, Kevin Whelan |
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| Rok vydání: | 2010 |
| Předmět: |
Male
Drug Inverse Agonism Administration Oral Biological Availability Pharmacology Piperazines Rats Sprague-Dawley Structure-Activity Relationship Dogs In vivo Sleep Initiation and Maintenance Disorders Drug Discovery Sleep research Insomnia medicine Animals Humans Receptor Sleep maintenance Chemistry Brain Blood Proteins Haplorhini Amides Rats Microsomes Liver Serotonin 5-HT2 Receptor Antagonists Molecular Medicine Pyrazoles Serotonin medicine.symptom Antagonism Sleep Protein Binding |
| Zdroj: | Journal of medicinal chemistry. 53(15) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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