4-fluorosulfonylpiperidines:: Selective 5-HT2A ligands for the treatment of insomnia

Incorporation of fluorine at the 4-position of an existing series of sulfonyl piperidine 5-HT2A antagonists gave compounds with increased selectivity over the IKr potassium channel. This work led to the identification of 3b, a compound that gave no increase in QT(c) in the anesthetized dog up to plasma levels as high as 148 mu M. Furthermore, 3b has been shown to increase slow-wave sleep bout duration and to decrease the number of awakenings in rats, indicating the potential utility of 5-HT2A antagonists in the treatment of insomnia. (c) 2005 Elsevier Ltd. All rights reserved.