Novel imidazobenzazepine derivatives as dual H1/5-HT2A antagonists for the treatment of sleep disorders.
A novel imidazobenzazepine template (5a) with potent dual H(1)/5-HT(2A) antagonist activity was identified. Application of a zwitterionic approach to this poorly selective and poorly developable starting point successfully delivered a class of high quality leads, 3-[4-(3-R(1)-2-R-5H-imidazo[1,2-b][2]benzazepin-11-yl)-1-piperazinyl]-2,2-dimethylpropanoic acids (e.g., 9, 19, 20, and 21), characterized by potent and balanced H(1)/5-HT(2A) receptor antagonist activities and good developability profiles.
Gianotti
Massimo
M
Neurosciences CEDD, GlaxoSmithKline, Medicines Research Centre, Verona, Italy. massimo.gianotti@aptuit.com
Corti
Corrado
C
Delle Fratte
Sonia
S
Di Fabio
Romano
R
Leslie
Colin P
CP
Pavone
Francesca
F
Piccoli
Laura
L
Stasi
Luigi
L
Wigglesworth
Mark J
MJ
D006801:Humans; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects*; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000627:therapeutic use*; D012893:Sleep Wake Disorders / Q000188:drug therapy*
D044402:Receptor, Serotonin, 5-HT2A; D012702:Serotonin Antagonists; D044282:Receptor, Serotonin, 5-HT1A