ABSTRACT
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.
Subject(s)
Imidazoles/pharmacology , Quinolines/pharmacology , Serotonin Antagonists/pharmacology , Administration, Oral , Animals , CHO Cells , Chromatography, Liquid , Cricetulus , Drug Discovery , Humans , Imidazoles/administration & dosage , Imidazoles/chemistry , Magnetic Resonance Spectroscopy , Male , Quinolines/administration & dosage , Quinolines/chemistry , Rats, Sprague-Dawley , Receptors, Serotonin/classification , Serotonin Antagonists/administration & dosage , Serotonin Antagonists/chemistry , Tandem Mass SpectrometryABSTRACT
A series of novel, non-basic 3-(6-chloronaphth-2-ylsulfonyl)aminopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating an alanylamide P4 group, was designed and synthesised. Within this series, the N-2-(morpholin-4-yl)-2-oxoethyl derivative 24 was shown to be a potent, selective fXa inhibitor with good anticoagulant activity. Moreover, 24 possessed highly encouraging rat and dog pharmacokinetic profiles with excellent oral bioavailabilities in both species.
