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.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Receptor, Serotonin, 5-HT2A/metabolism , Serotonin 5-HT2 Receptor Antagonists/chemistry , Serotonin 5-HT2 Receptor Antagonists/therapeutic use , Sleep Initiation and Maintenance Disorders/drug therapy , Sleep/drug effects , Animals , Humans , Rats , Serotonin 5-HT2 Receptor Antagonists/pharmacokinetics , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Amides/chemical synthesis , Piperazines/chemical synthesis , Pyrazoles/chemical synthesis , Serotonin 5-HT2 Receptor Antagonists , Sleep Initiation and Maintenance Disorders/drug therapy , Sleep/drug effects , Administration, Oral , Amides/pharmacokinetics , Amides/pharmacology , Animals , Biological Availability , Blood Proteins/metabolism , Brain/metabolism , Dogs , Drug Inverse Agonism , Haplorhini , Humans , Male , Microsomes, Liver/metabolism , Piperazines/pharmacokinetics , Piperazines/pharmacology , Protein Binding , Pyrazoles/pharmacokinetics , Pyrazoles/pharmacology , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
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.
