Novel Spirotetracyclic Zwitterionic Dual H1/5-HT2A Receptor Antagonists for the Treatment of Sleep Disorders

Histamine H1 and serotonin 5-HT2A receptors mediate two different mechanisms involved in sleep regulation: H1 antagonists are sleep inducers, while 5-HT2A antagonists are sleep maintainers. Starting from 9′a, a novel spirotetracyclic compound endowed with good H1/5-HT2A potency but poor selectivity, very high Cli, and a poor P450 profile, a specific optimization strategy was set up. In particular, we investigated the possibility of introducing appropriate amino acid moieties to optimize the developability profile of the series. Following this zwitterionic approach, we were able to identify several advanced leads (51, 65, and 73) with potent dual H1/5-HT2A activity and appropriate developability profiles. These compounds exhibited efficacy as hypnotic agents in a rat telemetric sleep model with minimal effective doses in the range 3−10 mg/kg po.