ABSTRACT
5-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}-2(1H)-quinolinones and 3,4-dihydro-2(1H)-quinolinones have been identified with different combinations of 5-HT(1) autoreceptor antagonist and hSerT potencies and excellent rat PK profiles. The availability of tool compounds with a range of profiles at targets known to play a key role in the control of synaptic 5-HT levels will allow exploration of different pharmacological profiles in a range of animal behavioral and disease models.
Subject(s)
Quinolones/chemistry , Receptors, Serotonin, 5-HT1/drug effects , Selective Serotonin Reuptake Inhibitors/chemistry , Selective Serotonin Reuptake Inhibitors/pharmacokinetics , Animals , Autoreceptors/antagonists & inhibitors , Autoreceptors/drug effects , Quinolones/pharmacokinetics , Rats , Selective Serotonin Reuptake Inhibitors/pharmacology , Synapses/chemistryABSTRACT
Bioisoteric replacement of the metabolically labile N-methyl amide group of a series of benzoxazinones with small heterocyclic rings has led to novel series of fused tricyclic benzoxazines which are potent 5-HT(1A/B/D) receptor antagonists with and without concomitant human serotonin transporter (hSerT) activity. Optimizing against multiple parameters in parallel identified 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazine-3-carboxamide (GSK588045) as a potent 5-HT(1A/B/D) receptor antagonist with a high degree of selectivity over human ether-a-go-go related gene (hERG) potassium channels, favorable pharmacokinetics, and excellent activity in vivo in rodent pharmacodynamic (PD) models. On the basis of its outstanding overall profile, this compound was progressed as a clinical candidate with the ultimate aim to assess its potential as a faster acting antidepressant/anxiolytic with reduced side-effect burden.
Subject(s)
Anti-Anxiety Agents/chemical synthesis , Antidepressive Agents/chemical synthesis , Benzoxazines/chemical synthesis , Serotonin 5-HT1 Receptor Antagonists , Animals , Anti-Anxiety Agents/pharmacokinetics , Anti-Anxiety Agents/pharmacology , Antidepressive Agents/pharmacokinetics , Antidepressive Agents/pharmacology , Benzoxazines/pharmacokinetics , Benzoxazines/pharmacology , Callithrix , Cell Line , Cerebral Cortex/metabolism , Cricetinae , Cricetulus , Cytochrome P-450 Enzyme System/metabolism , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/metabolism , Guinea Pigs , Humans , In Vitro Techniques , Male , Microsomes, Liver/metabolism , Protein Binding , Radioligand Assay , Rats , Rats, Sprague-Dawley , Serotonin Plasma Membrane Transport Proteins/metabolism , Structure-Activity RelationshipABSTRACT
8-[2-(4-Aryl-1-piperazinyl)ethyl]-2H-1,4-benzoxazin-3(4H)-ones have been identified as highly potent 5-HT(1A/B/D) receptor antagonists with and without additional SerT activity and a high degree of selectivity over hERG potassium channels. Modulation of the different target activities gave compounds with a range of profiles suitable for further in vivo characterization.
Subject(s)
Benzoxazines/chemistry , Piperazines/chemistry , Selective Serotonin Reuptake Inhibitors/chemistry , Serotonin 5-HT1 Receptor Antagonists , Serotonin Antagonists/chemistry , Animals , Benzoxazines/metabolism , Benzoxazines/pharmacology , CHO Cells , Cricetinae , Cricetulus , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Ether-A-Go-Go Potassium Channels/metabolism , Humans , Piperazines/metabolism , Piperazines/pharmacology , Rats , Receptors, Serotonin, 5-HT1/metabolism , Serotonin Antagonists/metabolism , Serotonin Antagonists/pharmacology , Selective Serotonin Reuptake Inhibitors/metabolism , Selective Serotonin Reuptake Inhibitors/pharmacologyABSTRACT
Investigation of a series 6-[2-(4-aryl-1-piperazinyl)ethyl]-2H-1,4-benzoxazin-3(4H)-ones has led to the discovery of potent 5-HT(1A/1B/1D) receptor antagonists with and without additional SerT affinity. Modulation of the different target activities gave compounds with a range of profiles suitable for further in vivo characterization.
