Synthesis and in Vivo Evaluation of Phenethylpiperazine Amides: Selective 5-Hydroxytryptamine(2A) Receptor Antagonists for the Treatment of Insomnia

• Published in: Journal of medicinal chemistry Vol. 53; no. 15; pp. 5696 - 5706
• Main Authors: Xiong, Yifeng, Ullman, Brett, Choi, Jin-Sun Karoline, Cherrier, Martin, Strah-Pleynet, Sonja, Decaire, Marc, Dosa, Peter I., Feichtinger, Konrad, Teegarden, Bradley R., Frazer, John M., Yoon, Woo H., Shan, Yun, Whelan, Kevin, Hauser, Erin K., Grottick, Andrew J., Semple, Graeme, Al-Shamma, Hussien
• Format: Journal Article
• Language: English
• Published: WASHINGTON Amer Chemical Soc 12.08.2010
• Subjects: Administration, Oral; Amides - chemical synthesis; Amides - pharmacokinetics; Amides - pharmacology; Animals; Biological Availability; Blood Proteins - metabolism; Brain - metabolism; Chemistry, Medicinal; Dogs; Drug Inverse Agonism; Haplorhini; Humans; Life Sciences & Biomedicine; Male; Microsomes, Liver - metabolism; Pharmacology & Pharmacy; Piperazines - chemical synthesis; Piperazines - pharmacokinetics; Piperazines - pharmacology; Protein Binding; Pyrazoles - chemical synthesis; Pyrazoles - pharmacokinetics; Pyrazoles - pharmacology; Rats; Rats, Sprague-Dawley; Science & Technology; Serotonin 5-HT2 Receptor Antagonists; Sleep - drug effects; Sleep Initiation and Maintenance Disorders - drug therapy; Structure-Activity Relationship; SLEEP; SEROTONIN; RAT; EMD-281014; 5-HT2A; AGONIST
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm100479q

Recent developments in sleep research suggest that antagonism of the serotonin 5-HT2A receptor may improve sleep maintenance insomnia. We herein report the discovery of a series of potent and selective serotonin 5-HT2A 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-HT2A receptor binding affinity, high selectivity over the 5-HT2C 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.