Fluorination of 3-(3-(piperidin-1-yl)propyl)indoles and 3-(3-(piperazin-1-yl)propyl)indoles gives selective human 5-HT1D receptor ligands with improved pharmacokinetic profiles

It has previously been reported that a 3-(3-(piperazin-1-yl)propyl)indole s eries of 5-HT1D receptor ligands have pharmacokinetic advantages over the-c orresponding 3-(3-(piperidin-1-yl)propyl)indole series and that the reduced pK(a) of the piperazines compared to the piperidines may be one possible e xplanation for these differences. To investigate this proposal we have deve loped versatile synthetic strategies for the incorporation of fluorine into these ligands, producing novel series of 4-fluoropiperidines, 3-fluoro-4-a minopiperidines, and both piperazine and piperidine derivatives with one or two fluorines in the propyl linker. Ligands were identified which maintain ed high affinity and selectivity for the 5-HT1D receptor and showed agonist efficacy in vitro. The incorporation of fluorine was found to significantl y reduce the pK(a) of the compounds, and this reduction of basicity was sho wn to have a dramatic, beneficial influence on oral absorption, although th e effect on oral bioavailability could not always be accurately predicted.