Model studies on a synthetically facile series of N-substituted phenyl-N'-pyridin-3-yl ureas leading to 1-(3-pyridylcarbamoyl) indolines that are potent and selective 5-HT(2C/2B) receptor antagonists.
A model series of 5-HT2C antagonists have been prepared by rapid parallel synthesis. These N-substituted phenyl-N'-pyridin-3-yl ureas were found to have a range of 5-HT2C receptor affinities and selectivities over the closely related 5-HT2A receptor. Extrapolation of simple SAR, derived from this set of compounds, to the more active but synthetically more complex 1-(3-pyridylcarbamoyl)indoline series allowed us to target optimal substitution patterns and identify potent and selective 5-HT(2C/2B) antagonists.
Bromidge
S M
SM
SmithKline Beecham Pharmaceuticals Discovery Research, New Frontiers Science Park, Harlow, Essex, UK. steve_bromidge-1@sbphrd.com
Dabbs
S
S
Davies
D T
DT
Davies
S
S
Duckworth
D M
DM
Forbes
I T
IT
Gadre
A
A
Ham
P
P
Jones
G E
GE
King
F D
FD
Saunders
D V
DV
Thewlis
K M
KM
Vyas
D
D
Blackburn
T P
TP
Holland
V
V
Kennett
G A
GA
Riley
G J
GJ
Wood
M D
MD
D000818:Animals; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D010671:Phenylurea Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D044403:Receptor, Serotonin, 5-HT2B; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D012702:Serotonin Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D010671:Phenylurea Compounds; D011725:Pyridines; D044403:Receptor, Serotonin, 5-HT2B; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists