RESUMEN
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.
Asunto(s)
Quinolonas/química , Receptores de Serotonina 5-HT1/efectos de los fármacos , Inhibidores Selectivos de la Recaptación de Serotonina/química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacocinética , Animales , Autorreceptores/antagonistas & inhibidores , Autorreceptores/efectos de los fármacos , Quinolonas/farmacocinética , Ratas , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Sinapsis/químicaRESUMEN
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.
Asunto(s)
Ansiolíticos/síntesis química , Antidepresivos/síntesis química , Benzoxazinas/síntesis química , Antagonistas del Receptor de Serotonina 5-HT1 , Animales , Ansiolíticos/farmacocinética , Ansiolíticos/farmacología , Antidepresivos/farmacocinética , Antidepresivos/farmacología , Benzoxazinas/farmacocinética , Benzoxazinas/farmacología , Callithrix , Línea Celular , Corteza Cerebral/metabolismo , Cricetinae , Cricetulus , Sistema Enzimático del Citocromo P-450/metabolismo , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/metabolismo , Cobayas , Humanos , Técnicas In Vitro , Masculino , Microsomas Hepáticos/metabolismo , Unión Proteica , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Relación Estructura-ActividadRESUMEN
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.