Phenyl benzenesulfonamides are novel and selective 5-HT6 antagonists: identification of N-(2,5-dibromo-3-fluorophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide (SB-357134).
Substituted N-phenyl-4-methoxy-3-piperazin-1-ylbenzenesulfonamides and conformationally restricted analogues have been identified as high affinity and selective 5-HT6 antagonists. Compounds from this series had a range of pharmacokinetic profiles in rat and in general there was a correlation between clearance and CNS penetration. Based on its overall biological profile 2 (SB-357134) was selected for further pre-clinical evaluation.
Bromidge
S M
SM
Discovery Chemistry Europe, SmithKline Beecham Pharmaceuticals, Discovery Research, Harlow, Essex, UK. steve_bromidge-1@sbphrd.com
Clarke
S E
SE
Gager
T
T
Griffith
K
K
Jeffrey
P
P
Jennings
A J
AJ
Joiner
G F
GF
King
F D
FD
Lovell
P J
PJ
Moss
S F
SF
Newman
H
H
Riley
G
G
Rogers
D
D
Routledge
C
C
Serafinowska
H
H
Smith
D R
DR
D000818:Animals; D001682:Biological Availability; D001812:Blood-Brain Barrier / Q000502:physiology; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D010879:Piperazines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D011985:Receptors, Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000096926:Benzenesulfonamides
D010879:Piperazines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013449:Sulfonamides; C422502:N-(2,5-dibromo-3-fluorophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide; D000096926:Benzenesulfonamides; C097216:serotonin 6 receptor