4-Fluorosulfonylpiperidines: selective 5-HT2A ligands for the treatment of insomnia.
Bioorganic & medicinal chemistry letters 2005 Aug 15; 15(16):3665-9
Fish L LR, Gilligan M MT, Humphries A AC, Ivarsson M M, Ladduwahetty T T, Merchant K KJ, O'connor D D, Patel S S, Philipps E E, Vargas H HM, Hutson P PH, Macleod A AM
The Neuroscience Research Centre, Merck Sharp and Dohme, Terlings Park, Harlow, Essex CM20 2QR, UK.
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 microM. 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.