RESUMEN
(R)-3-(4-propylmorpholin-2-yl) phenol (PF-219061) is a potent, selective agonist of the dopamine 3 receptor for the treatment of female sexual dysfunction. In vivo, PF-219061 exhibits liver blood flow clearance in both rat and dog. Oral bioavailability was 0.7% in dog and less than 5% in rat. Intranasal dosing was investigated to improve bioavailability. Pre-clinical assessments in rat and dog demonstrated intranasal bioavailabilities of 16-38% in rat and 54-61% in dog with very rapid absorption. It was predicted that an intranasal dose in man would give approximately 25-50% bioavailability. The clinical data verified the preclinical predictions demonstrating rapid absorption and approximately dose-proportional increases in exposure. The intranasal bioavailability in man was estimated to be 26-38%. These findings indicate the potential utility of intranasal dosing as a route that circumvents the first-pass effects for PF-219061 resulting in high exposures.
Asunto(s)
Antagonistas de Dopamina/farmacocinética , Morfolinas/farmacocinética , Fenoles/farmacocinética , Receptores de Dopamina D3/antagonistas & inhibidores , Administración Intranasal , Adsorción , Animales , Disponibilidad Biológica , Células CACO-2 , Perros , Antagonistas de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Morfolinas/farmacología , Fenoles/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D3/metabolismo , Disfunciones Sexuales Fisiológicas/tratamiento farmacológicoRESUMEN
It has previously been reported that a 3-(3-(piperazin-1-yl)propyl)indole series of 5-HT1D receptor ligands have pharmacokinetic advantages over the corresponding 3-(3-(piperidin-1-yl)propyl)indole series and that the reduced pKa of the piperazines compared to the piperidines may be one possible explanation for these differences. To investigate this proposal we have developed versatile synthetic strategies for the incorporation of fluorine into these ligands, producing novel series of 4-fluoropiperidines, 3-fluoro-4-aminopiperidines, and both piperazine and piperidine derivatives with one or two fluorines in the propyl linker. Ligands were identified which maintained high affinity and selectivity for the 5-HT1D receptor and showed agonist efficacy in vitro. The incorporation of fluorine was found to significantly reduce the pKa of the compounds, and this reduction of basicity was shown to have a dramatic, beneficial influence on oral absorption, although the effect on oral bioavailability could not always be accurately predicted.