RESUMO
The discovery and structure-activity relationship of a series of hA(2A) receptor antagonists is described. Compound 28 was selected from the series as a potent and selective compound and was shown to be efficacious in an in vivo model of Parkinson's disease. It had acceptable ADME properties; however, the low intrinsic solubility of this compound was limiting for its developability, because the oral bioavailability from dosing in suspension was significantly lower than the oral bioavailability from solution dosage. As a consequence, prodrugs of 28 were prepared with dramatically increased aqueous solubility. The prodrugs efficiently delivered 28 into systemic circulation, with no detectable levels of prodrug in plasma samples. From this investigation, we selected 32 (Lu AA47070), a phosphonooxymethylene prodrug of 28, as a drug candidate.
Assuntos
Antagonistas do Receptor A2 de Adenosina/síntese química , Antiparkinsonianos/síntese química , Organofosfatos/síntese química , Pró-Fármacos/síntese química , Tiazóis/síntese química , Antagonistas do Receptor A2 de Adenosina/farmacocinética , Antagonistas do Receptor A2 de Adenosina/farmacologia , Animais , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/farmacologia , Células CHO , Células CACO-2 , Permeabilidade da Membrana Celular , Cricetinae , Cricetulus , Cristalografia por Raios X , Ensaios de Triagem em Larga Escala , Humanos , Masculino , Camundongos , Modelos Moleculares , Organofosfatos/farmacocinética , Organofosfatos/farmacologia , Pró-Fármacos/farmacocinética , Pró-Fármacos/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Solubilidade , Estereoisomerismo , Relação Estrutura-Atividade , Tiazóis/farmacocinética , Tiazóis/farmacologia , ÁguaRESUMO
The effects of five antidepressants (escitalopram, paroxetine, duloxetine, venlafaxine, and reboxetine) on the sleep architecture were investigated in freely moving rats in the light phase of a 12:12 h light:dark cycle following a single i.p. dose of antidepressant. Overall, paroxetine and escitalopram exhibited the least sleep disruptive profiles, whereas duloxetine, venlafaxine, and reboxetine increased the time spent awake and suppressed paradoxical sleep. Analysis of the EEG at 1 h intervals revealed only subtle differences from the overall picture. The effect of venlafaxine on disruption of sleep architecture could not be readily explained by its in vitro serotonin (5-HT) and noradrenaline (NA) reuptake inhibitory potencies. In vivo microdialysis experiments in the ventral hippocampus of freely moving rats revealed that venlafaxine affected the 5-HT and NA systems equally at the doses tested. Duloxetine (7.7 mg/kg) induced maximal blockade of the 5-HT transporter and duloxetine 7.7 mg/kg also modulated the noradrenaline system. Thus, in this animal model, the enhancement of noradrenergic activity is more disruptive on the sleep architecture than enhancement of serotonergic activity.