4-Fluorosulfonylpiperidines: selective 5-HT2A ligands for the treatment of insomnia.
Fish LR,
Gilligan MT,
Humphries AC,
Ivarsson M,
Ladduwahetty T,
Merchant KJ,
O'Connor D,
Patel S,
Philipps E,
Vargas HM,
Hutson PH,
MacLeod 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.
PMID: 15993598 [PubMed - indexed for MEDLINE]