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 QTc in the anesthetized dog up to plasma levels as high as 148 μM. 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.

Graphical abstractα-Fluorosulfones, of general structure 3, were synthesized as an alternative approach to reduce the pKa of the piperidine ring in an existing series of sulfonyl piperidine 5-HT2A antagonists. This work led to the identification of 3b, a selective 5-HT2A antagonist that gave no significant increase in QTc in the anesthetized dog.Figure optionsDownload full-size imageDownload as PowerPoint slide