Fluorination of 3-(3-(Piperidin-1-yl)propyl)indoles and 3-(3-(Piperazin-1-yl)propyl)indoles Gives Selective Human 5-HT<sub>1D</sub> Receptor Ligands with Improved Pharmacokinetic Profiles

Monique B. van Niel , Ian Collins , Margaret S. Beer , Monique B. van Niel , Ian Collins , Margaret S. Beer , Howard B. Broughton , Susan K. F. Cheng , Simon Goodacre , Anne Heald , Karen L Locker , Angus M. MacLeod , Denise Morrison , Christopher R. Moyes , Desmond O’Connor , Andrew Pike , Michael Rowley , Michael G. N. Russell , Balbinder Sohal , Josephine A. Stanton , Steven R. Thomas , Hugh Verrier , Alan P. Watt , José L. Castro
1999 Journal of Medicinal Chemistry 156 citations

Abstract

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.

Keywords

ChemistryPiperazinePiperidineIndole testLinkerBioavailabilityAgonistSelectivityPharmacokineticsChemical synthesisStereochemistryLipophilicityPartial agonistReceptorCombinatorial chemistryIn vitroPharmacologyOrganic chemistryBiochemistry

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Year
1999
Type
article
Volume
42
Issue
12
Pages
2087-2104
Citations
156
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Monique B. van Niel, Ian Collins, Margaret S. Beer et al. (1999). Fluorination of 3-(3-(Piperidin-1-yl)propyl)indoles and 3-(3-(Piperazin-1-yl)propyl)indoles Gives Selective Human 5-HT<sub>1D</sub> Receptor Ligands with Improved Pharmacokinetic Profiles. Journal of Medicinal Chemistry , 42 (12) , 2087-2104. https://doi.org/10.1021/jm981133m

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DOI
10.1021/jm981133m