191351-72-1Relevant articles and documents
Fluorination of 3-(3-(piperidin-1-yl)propyl)indoles and 3-(3-(piperazin- 1-yl)propyl)indoles gives selective human 5-HT(1D) receptor ligands with improved pharmacokinetic profiles
Van Niel, Monique B.,Collins, Ian,Beer, Margaret S.,Broughton, Howard B.,Cheng, Susan K. F.,Goodacre, Simon C.,Heald, Anne,Locker, Karen L.,MacLeod, Angus M.,Morrison, Denise,Moyes, Christopher R.,O'Connor, Desmond,Pike, Andrew,Rowley, Michael,Russell, Michael G. N.,Sohal, Baibinder,Stanton, Josephine A.,Thomas, Steven,Verrier, Hugh,Watt, Alan P.,Castro, José L.
, p. 2087 - 2104 (1999)
It has previously been reported that a 3-(3-(piperazin-1- yl)propyl)indole series of 5-HT(1D) receptor ligands have pharmacokinetic advantages over the corresponding 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 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-HT(1D) receptor and showed agonist efficacy in vitro. The incorporation of fluorine was found to significantly reduce the pK(a) 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.
