Bicyclic heteroarylpiperazines as selective brain penetrant 5-HT6 receptor antagonists.
Starting from the potent and selective but poorly brain penetrant 5-HT6 receptor antagonist SB-271046, a successful strategy for improving brain penetration was adopted involving conformational constraint with concomitant reduction in hydrogen bond count. This provided a series of bicyclic heteroarylpiperazines with high 5-HT6 receptor affinity. 5-Chloroindole 699929 combined high 5-HT6 receptor affinity with excellent brain penetration and also had good oral bioavailability in both rat and dog.
Ahmed
Mahmood
M
Neurology and GI Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.
Briggs
Michael A
MA
Bromidge
Steven M
SM
Buck
Tania
T
Campbell
Lorraine
L
Deeks
Nigel J
NJ
Garner
Ashley
A
Gordon
Laurie
L
Hamprecht
Dieter W
DW
Holland
Vicky
V
Johnson
Christopher N
CN
Medhurst
Andrew D
AD
Mitchell
Darren J
DJ
Moss
Stephen F
SF
Powles
Jenifer
J
Seal
Jon T
JT
Stean
Tania O
TO
Stemp
Geoffrey
G
Thompson
Mervyn
M
Trail
Brenda
B
Upton
Neil
N
Winborn
Kim
K
Witty
David R
DR
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D004285:Dogs; D008968:Molecular Conformation; D010539:Permeability; D010879:Piperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D010879:Piperazines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C097216:serotonin 6 receptor