Discovery of 1-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone (GSK163090), a Potent, selective, and orally active 5-HT1A/B/D receptor antagonist.
In an effort to identify selective drug like pan-antagonists of the 5-HT1 autoreceptors, studies were conducted to elaborate a previously reported dual acting 5-HT1 antagonist/SSRI structure. A novel series of compounds was identified showing low intrinsic activities and potent affinities across the 5-HT1A, 5-HT1B, and 5-HT1D receptors as well as high selectivity against the serotonin transporter. From among these compounds, 1-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone (36) was found to combine potent in vivo activity with a strong preclinical developability profile, and on this basis it was selected as a drug candidate with the aim of assessing its potential as a fast-onset antidepressant/anxiolytic.
Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline SpA, Medicines Research Centre, Via A. Fleming 4, 37135 Verona, Italy.
Colin P
CP
Leslie
Matteo
M
Biagetti
Silvia
S
Bison
Steven M
SM
Bromidge
Romano
R
Di Fabio
Daniele
D
Donati
Alessandro
A
Falchi
Martine J
MJ
Garnier
Albert
A
Jaxa-Chamiec
Gary
G
Manchee
Giancarlo
G
Merlo
Domenica A
DA
Pizzi
Luigi P
LP
Stasi
Jessica
J
Tibasco
Antonio
A
Vong
Simon E
SE
Ward
Laura
L
Zonzini
D000284:Administration, Oral; D000818:Animals; D016466:CHO Cells; D002853:Chromatography, Liquid; D003412:Cricetulus; D055808:Drug Discovery; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D011804:Quinolines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000145:classification; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D053719:Tandem Mass Spectrometry
C587791:1-(3-(2-(4-(2-methyl-5-quinolinyl)-1-piperazinyl)ethyl)phenyl)-2-imidazolidinone; D007093:Imidazoles; D011804:Quinolines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists