Discovery of 1-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone (GSK163090), a Potent, Selective, and Orally Active 5-HT(1A/B/D) Receptor Antagonist.

In an effort to identify selective drug like pan-antagonists of the 5-HT(1) autoreceptors, studies were conducted to elaborate a previously reported dual acting 5-HT(1) antagonist/SSRI structure. A novel series of compounds was identified showing low intrinsic activities and potent affinities across the 5-HT(1A), 5-HT(1B), and 5-HT(1D) 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.