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 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.
Fish
L Rebecca
LR
The Neuroscience Research Centre, Merck Sharp and Dohme, Terlings Park, Harlow, Essex CM20 2QR, UK.
Gilligan
Myra T
MT
Humphries
Alexander C
AC
Ivarsson
Magnus
M
Ladduwahetty
Tammy
T
Merchant
Kevin J
KJ
O'Connor
Desmond
D
Patel
Smita
S
Philipps
Elisabeth
E
Vargas
Hugo M
HM
Hutson
Peter H
PH
MacLeod
Angus M
AM
D000818:Animals; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D008024:Ligands; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use*; D051381:Rats; D058830:Serotonin 5-HT2 Receptor Antagonists; D007319:Sleep Initiation and Maintenance Disorders / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D013997:Time Factors
D008024:Ligands; D010880:Piperidines; D058830:Serotonin 5-HT2 Receptor Antagonists